Opioid agonist formulations with releasable and sequestered antagonist

ABSTRACT

Disclosed are oral dosage forms, comprising (i) a therapeutically effective amount of an opioid agonist; (ii) an opioid antagonist in releasable form; and (iii) a sequestered opioid antagonist which is not released when the dosage form is administered intact, and methods thereof.

[0001] This application claims priority from U.S. ProvisionalApplication Serial No. 60/310,536 filed Aug. 6, 2001, the disclosure ofwhich is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Opioid formulations are sometimes the subject of abuse. Aparticular dose of oxycodone may be more potent when administeredparenterally as compared to the same dose administered orally. Also,some formulations can be tampered with in order to provide the opioidagonist contained therein better available for illicit use. For example,a controlled release opioid agonist formulation can be crushed in orderto provide the opioid contained therein available for immediate releaseupon oral or parenteral administration. An opioid formulation can alsobe abusable by administration of more than the prescribed dose of thedrug.

[0003] Opioid antagonists have been combined with certain opioidagonists in order to deter the parenteral abuse of opioid agonists. Inthe prior art, the combination of immediate release pentazocine andnaloxone has been utilized in tablets available in the United States,commercially available as Talwin®Nx from Sanofi-Winthrop. Talwin®Nxcontains immediate release pentazocine hydrochloride equivalent to 50 mgbase and naloxone hydrochloride equivalent to 0.5 mg base. A fixedcombination therapy comprising tilidine (50 mg) and naloxone (4 mg) hasbeen available in Germany for the management of pain since 1978(Valoron®N, Goedecke). A fixed combination of buprenorphine and naloxonewas introduced in 1991 in New Zealand (Temgesic®Nx, Reckitt & Colman)for the treatment of pain.

[0004] Purdue Pharma L.P currently markets sustained-release oxycodonein dosage forms containing 10, 20, 40 and 160 mg oxycodone hydrochlorideunder the tradename OxyContin.

[0005] U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656,295disclose sustained release oxycodone formulations.

[0006] U.S. Pat. Nos. 4,769,372 and 4,785,000 to Kreek describe methodsof treating patients suffering from chronic pain or chronic coughwithout provoking intestinal dysmotility by administering 1 to 2 dosageunits comprising from about 1.5 to about 100 mg of opioid analgesic orantitussive and from about 1 to about 18 mg of an opioid antagonisthaving little to no systemic antagonist activity when administeredorally, from 1 to 5 times daily.

[0007] U.S. Pat. No. 6,228,863 to Palermo et al. describes compositionsand methods of preventing abuse of opioid dosage forms.

[0008] WO099/32119 to Kaiko et al. describes compositions and methods ofpreventing abuse of opioid dosage forms.

[0009] U.S. Pat. No. 5,472,943 to Crain et al. describes methods ofenhancing the analgesic potency of bimodally acting opioid agonists byadministering the agonist with an opioid antagonist.

[0010] All documents cited herein, including the foregoing areincorporated by reference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

[0011] It is an object of the invention to provide an oral dosage formof an opioid agonist that is useful for decreasing the potential forabuse of the opioid agonist contained therein.

[0012] It is an object of certain embodiments of the invention toprovide an oral dosage form of an opioid agonist that is useful fordecreasing the potential abuse of the opioid agonist without affectingthe analgesic effects of the opioid agonist or incurring the risk ofprecipitating withdrawal if taken intact.

[0013] It is an object of certain embodiments of the invention toprovide an oral dosage form of an opioid agonist that is resistant tomisuse, abuse or diversion, wherein said resistance does not depend onindividual patient-specific differences in the effects ofco-administered opioid agonist and antagonist mixtures.

[0014] It is an object of certain embodiments of the invention toprovide an oral dosage form containing an effective dose of an opioidagonist along with a dose of opioid antagonist which does not change theanalgesic efficacy of the opioid agonist when the dosage form is orallyadministered intact, but which can prevent abuse if the dosage form istampered with by interfering with the effect of the opioid agonist.

[0015] It is an object of certain embodiments of the invention toprovide a method for preventing abuse of an oral opioid dosage formwhere the dosage form also includes a dose of opioid antagonist which issequestered, e.g., is not bioavailable when the dose is administeredintact but is bioavailable when the dosage form is tampered with (e.g.,in an attempt to misuse the dose of opioid analgesic) and a dose ofantagonist which is releasable to provide a desired effect.

[0016] It is an object of certain embodiments of the invention toprovide oral dosage forms that are intended for or are suitable for usein the management of acute or chronic pain where alteration of theopioid agonist's analgesic affects must be avoided such as in cases oftolerance, physical dependence or individual variability in hepaticmetabolism or physiology.

[0017] It is a further object of a preferred embodiment of the inventionto provide a method of treating pain in human patients with an oraldosage form of an opioid agonist while reducing its misuse by oral,parenteral, intranasal and/or sublingual route.

[0018] It is an object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless abuse potential via the oral route than prior commerciallyavailable dosage forms.

[0019] It is an object of certain embodiments of the present inventionto provide an oral dosage form of an opioid analgesic and method whichprovides therapeutic analgesia and which also provides a negative,“aversive” experience when the prescribed amount or a large amount ofthe opioid, e.g., about 2-3 times the usually prescribed dose, is takenby or administered to a physically dependent subject.

[0020] It is an object of certain embodiments of the present inventionto provide an oral dosage form of an opioid analgesic and a method forproviding therapeutic analgesia in a manner which is not as positivelyreinforcing in non-physically dependent subjects taking the same or morethan the usually prescribed dose, e.g., about 2-3 times the usuallyprescribed dose of the opioid, as compared to the same amount of opioidwithout the antagonist.

[0021] It is an object of certain embodiments of the invention toprovide a method of treating pain in human patients with an oral dosageform of an opioid analgesic while reducing the oral abuse potential ofdosage form.

[0022] It is an object of certain embodiments of the invention toprovide a method of manufacturing an oral dosage form of an opioidanalgesic such that it has less oral abuse potential.

[0023] It is an object of certain embodiments of the invention toprovide a composition and method of enhancing the analgesic potency ofopioid agonists by blocking their anti-analgesic side-effects.

[0024] It is an object of certain embodiments of the invention toprovide a composition and method of attenuating physical dependence,tolerance, hyperexcitability, hyperalgesia and other undesirableside-effects caused by the chronic administration of opioid agonists.

[0025] It is an object of certain embodiments of the invention toprovide a composition and method for detoxifying and treating opiateaddicts utilizing opioid receptor antagonists.

[0026] It is an object of certain embodiments of the invention toprovide a composition which enhances the analgesic effects of opioidagonists while simultaneously attenuating undesirable side-effectscaused by said opioid agonists, including physical dependence,tolerance, hyperexcitability and hyperalgesia.

[0027] Some or all of the above objects are achieved by the presentinvention which is directed to an oral dosage form, comprising (i) atherapeutically effective amount of an opioid agonist; (ii) an opioidantagonist in releasable form; and (iii) a sequestered opioid antagonistwhich is not released when the dosage form is administered intact.

[0028] Certain embodiments of the invention are directed to an oraldosage form, comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist; (ii) a secondcomponent comprising an opioid antagonist in releasable form; and (iii)a third component comprising a sequestered opioid antagonist which isnot released when the dosage form is administered intact.

[0029] Certain embodiments of the invention are directed to an oraldosage form comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist; (ii) a secondcomponent comprising an opioid antagonist in releasable form, and asequestered opioid antagonist which is not released when the dosage formis administered intact.

[0030] Certain embodiments of the invention are directed to an oraldosage form, comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist and an opioidantagonist in releasable form; and (ii) a second component comprising asequestered opioid antagonist which is not released when the dosage formis administered intact.

[0031] Certain embodiments of the invention are directed to an oraldosage form, comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist and an opioidantagonist in releasable form; and (ii) a second component comprising asequestered opioid antagonist which is not substantially released whenthe dosage form is administered intact.

[0032] Certain embodiments of the invention are directed to an oraldosage form, comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist; (ii) a secondcomponent comprising an opioid antagonist in releasable form; and (iii)a third component comprising a sequestered opioid antagonist which isnot substantially released when the dosage form is administered intact.

[0033] Certain embodiments of the present invention is directed to adosage form formulated such that the ratio of the amount of antagonistreleased from the dosage form after tampering to the amount of theantagonist released from the intact dosage form is about 3:1 or greater,based on the in-vitro dissolution at 1 hour of the dosage form in 900 mlof Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75rpm at 37 degrees C.

[0034] In embodiments of the invention wherein the antagonist innon-releasable form can be in the form of multiparticulates coated witha sequestering material, the multiparticulates can be in the form ofinert beads coated with the antagonist and overcoated with the material,or alternatively in the form of a granulation comprising the antagonistand the material. The multiparticulates can be dispersed in a matrixcomprising the opioid agonist or contained in a capsule with the opioidagonist.

[0035] In embodiments of the invention wherein the antagonist isdispersed in a matrix comprising a sequestering material whichsubstantially prevents the release of the antagonist, the matrix can bein the form of pellets. The pellets can be dispersed in another matrixcomprising the opioid agonist or contained in a capsule with the opioidagonist.

[0036] In other embodiments of the invention, part of the antagonist isin a matrix and/or part of the antagonist is in a coated bead.

[0037] In certain embodiments of the invention which exhibit theabove-disclosed ratio of about 3:1 or greater concerning the amount ofantagonist released from the dosage form after tampering to the amountof said antagonist released from the intact dosage form based on thedissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C.,the intact dosage form releases 22.5% or less of the antagonist after 1hour and the tampered dosage form releases 67.5% or more antagonistafter 1 hour. In another embodiment, the intact dosage form releases 20%or less of said antagonist after 1 hour and the tampered dosage formreleases 60% or more antagonist after 1 hour. In another embodiment, theintact dosage form releases 10% or less of said antagonist after 1 hourand the intact dosage form releases 5% or less of said antagonist after1 hour and the tampered dosage form releases 15% or more antagonistafter 1 hour.

[0038] In certain embodiments of the invention, the ratio of the amountof antagonist released from the dosage form after tampering to theamount of said antagonist released from the intact dosage form based onthe dissolution at 1 hour of the dosage form in 900 ml of SimulatedGastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37degrees C. is 4:1 or greater, 10:1 or greater, 50:1 or greater or 100:1or greater.

[0039] The invention is also directed to methods of preventing abuse ofan opioid agonist utilizing the dosage forms disclosed herein. Themethod can comprise providing the opioid agonist in an oral dosage formtogether with an opioid antagonist in non-releasable form upon digestionwhen the integrity of the dosage form is maintained until digestionbegins, but which becomes bioavialable if subjected to tampering (e.g.,crushing, shear forces which break up the dosage form, etc., solvents ortemperatures of greater than 45° C.).

[0040] Another embodiment of the invention is directed to a method ofdecreasing the abuse of an opioid agonist in an oral dosage form,comprising preparing an oral dosage form as disclosed herein. Forexample, the method can comprise preparing a dosage form comprising anopioid antagonist in non-releasable form such that said dosage formprovides a desired analgesic effect and said antagonist does notsubstantially block the analgesic effect of the opioid agonist when saiddosage form is administered orally intact. In alternative embodiments,the effect of the opioid agonist is at least partially blocked when saiddosage form tampered with, e.g., chewed, crushed or dissolved in asolvent, and administered orally, intranasally, parenterally orsublingually.

[0041] The invention is also directed to a method of treating pain withthe dosage forms disclosed herein.

[0042] The invention is also directed to methods of preparing the dosageforms disclosed herein. In certain embodiments, the invention comprisesa method of preparing an oral dosage form comprising pretreating anopioid antagonist to render it non-releasable; and combining thepretreated antagonist with a releasable form of an opioid agonist and anopioid antagonist in a manner that maintains the integrity of thenon-releasable form of the antagonist.

[0043] Certain embodiments of the invention are directed to formulationswherein the agonist, releasable antagonist and non-releasable antagonistare interdispersed and are not isolated from each other in threedistinct layers. Certain embodiments have two of the three agentsinterdispersed with the third in a separate and distinct layer. In otherembodiments, at least two or all of the ingredients are partiallyinterdispersed. The present invention contemplates all combinations ofthe agents interdispersed or partially interdispersed in anycombination.

[0044] The term “analgesic effectiveness” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with a tolerable level of side effects, as determined by the humanpatient. The phrase “not substantially blocking the analgesic effect ofan opioid agonist” means that the opioid antagonist does not block theeffects of the opioid agonist in sufficient degree as to render thedosage form therapeutically less effective for providing analgesia.

[0045] The term “an opioid antagonist in a substantially non-releasableform” refers to an opioid antagonist that is not released orsubstantially not released at one hour after the intact dosage formcontaining both opioid agonist and the opioid antagonist is orallyadministered (i.e., without having been tampered with). For purposes ofthe invention, the amount released after oral administration of theintact dosage form may be measured in-vitro via the dissolution at 1hour of the dosage form in 900 ml of Simulated Gastric Fluid using a USPType II (paddle) apparatus at 75 rpm at 37 degrees C. Such a dosage formis also referred to as comprising a “sequestered antagonist”.

[0046] Although the preferred embodiments of the invention comprise anopioid antagonist in a form that completely prevents the release of theopioid antagonist, the invention also includes an antagonist in asubstantially non-releasable form. The term “substantially not released”refers to the antagonist that might be released in a small amount, aslong as the amount released does not affect or does not significantlyaffect analgesic efficacy when the dosage form is orally administered tohumans as intended.

[0047] In certain preferred embodiments of the invention, thesubstantially non-releasable form of the antagonist is resistant tolaxatives (e.g., mineral oil) used to manage delayed colonic transit andto achlorhydric states.

[0048] In certain embodiments, the substantially non-releasable form ornon-releasable form of an opioid antagonist comprises an opioidantagonist that is formulated with one or more of pharmaceuticallyacceptable hydrophobic materials, such that the antagonist is notreleased or substantially not released during its transit through thegastrointestinal tract when administered orally as intended, withouthaving been tampered with.

[0049] In certain embodiments of the present invention, thesubstantially non-releasable form or non-releasable form of the opioidantagonist is vulnerable to mechanical, thermal and/or chemicaltampering, e.g., tampering by means of crushing, shearing, grinding,chewing and/or dissolution in a solvent in combination with heating(e.g., greater than about 45° C.) of the oral dosage form. When thustampered with, the integrity of the substantially non-releasable form ornon-releasable form of the opioid antagonist will be compromised, andthe opioid antagonist will be made available to be released. In certainembodiments, when the dosage form is chewed, crushed or dissolved andheated in a solvent, and administered orally, intranasally, parenterallyor sublingually, the analgesic or euphoric effect of the opioid isreduced or eliminated. In certain embodiments, the effect of the opioidagonist is at least partially blocked by the opioid antagonist. Incertain other embodiments, the effect of the opioid agonist issubstantially blocked by the opioid antagonist.

[0050] In certain embodiments, the quantity of antagonist released fromthe dosage form is in a ratio to the agonist which is aversive inphysically dependent human subjects when the dosage form is administeredat the same amount or at a higher amount than the therapeuticallyeffective amount

[0051] In certain embodiments, the quantity of the antagonist releasedfrom the first component is in an amount sufficient to be aversive inphysically dependent human subjects when the dosage form is administeredat the same amount or at a higher amount than the therapeuticallyeffective amount.

[0052] In certain embodiments, the quantity of the antagonist releasedfrom the first component is less than the amount sufficient to beaversive in physically dependent human subjects when the dosage form isadministered at the same amount or at a higher amount than thetherapeutically effective amount.

[0053] In certain embodiments, the amount of the antagonist releasedfrom the second component is in an amount sufficient to be aversive inphysically dependent human subjects when the dosage form is administeredat the same amount or at a higher amount than the therapeuticallyeffective amount.

[0054] In certain embodiments, the amount of the antagonist releasedfrom the second component is less than the amount sufficient to beaversive in physically dependent human subjects when the dosage form isadministered at the same amount or at a higher amount than thetherapeutically effective amount.

[0055] In certain embodiments, the invention comprises a sustainedrelease excipient which provides a sustained release of the opioidagonist.

[0056] In certain embodiments, the invention comprises a sustainedrelease excipient which provides a sustained release of the releasableopioid antagonist.

[0057] In certain embodiments, the invention comprises a sustainedrelease excipient which provides a sustained release of the opioidagonist and the opioid antagonist.

[0058] In certain embodiments, the sequestered antagonist is in the formof multiparticulates individually coated with a material that preventsrelease of the sequestered antagonist.

[0059] In certain embodiments, the sequestered antagonist is in the formof multiparticulates individually coated with a material thatsubstantially prevents release of the sequestered antagonist.

[0060] In certain embodiments, the sequestered antagonist is dispersedin a matrix comprising a sequestering material that prevents the releaseof the sequestered antagonist.

[0061] In certain embodiments, the sequestered antagonist is dispersedin a matrix comprising a sequestering material that substantiallyprevents the release of the sequestered antagonist.

[0062] In certain embodiments, the releasable opioid antagonist is thesame as the sequestered antagonist.

[0063] In certain embodiments, the releasable opioid antagonist isdifferent than the sequestered antagonist.

[0064] In certain embodiments, the antagonist is selected from the groupconsisting of naltrexone, naloxone, nalmephene, cyclazocine,levallorphan, pharmaceutically acceptable salts thereof and mixturesthereof.

[0065] In certain embodiments, the releasable antagonist is selectedfrom the group consisting of naltrexone, naloxone, nalmephene,cyclazocine, levallorphan, pharmaceutically acceptable salts thereof andmixtures thereof and the sequestered antagonist is selected from thegroup consisting of naltrexone, naloxone, nalmephene, cyclazocine,levallorphan, pharmaceutically acceptable salts thereof and mixturesthereof.

[0066] In certain embodiments, the opioid is selected from the groupconsisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine,levorphanol, meperidine, methadone, pharmaceutically acceptable saltsthereof and mixtures thereof.

[0067] In certain embodiments, the releasable antagonist is anantagonist with minimal oral activity such as naloxone in releasable or“non-sequestered” form and the sequestered antagonist is an orallybioavailable antagonist such as naltrexone. Such a dosage form would bea deterrent to parenteral, nasal and oral abuse of the dosage form uponadministration , of a tampered dosage form. The inclusion of thereleasable non-orally bioavailable antagonist with the opioid agonistwould make the formulation more resistant to abuse by making theformulation resistant to parenteral abuse even if the sequesteredantagonist was separated from the dosage form, while not affecting theagonist if administered intact.

[0068] In certain embodiments, the dosage form has a ratio of releasableopioid antagonist to opioid agonist that is analgesically effective whenthe combination is administered orally, but which is aversive inphysically dependent human subjects when administered at the same amountor at a higher amount than the therapeutically effective amount.

[0069] In certain embodiments, the ratio of releasable opioid antagonistto opioid agonist maintains an analgesic effect but does not increaseanalgesic efficacy of the opioid agonist relative to the sametherapeutic amount of opioid analgesic when administered to humanpatients without the opioid antagonist.

[0070] In certain embodiments, the opioid agonist is oxycodone and thereleasable antagonist is naltrexone.

[0071] In certain embodiments, the ratio of releasable naltrexone tohydrocodone is from about 0.03:1 to about 0.27:1.

[0072] In certain embodiments, the ratio of releasable naltrexone tohydrocodone is from about 0.05:1 to about 0.20:1.

[0073] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is oxycodone, wherein the ratio ofreleasable naltrexone to oxycodone is from about 0.037:1 to about0.296:1.

[0074] In certain embodiments, the releasable opioid antagonist isnaltrexone and the releasable opioid agonist is codeine, wherein theratio of releasable naltrexone to codeine is from about 0.005:1 to about0.044:1.

[0075] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is hydromorphone, wherein the ratio ofreleasable naltrexone to hydromorphone is from about 0.148:1 to about1.185:1.

[0076] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is levorphanol, wherein the ratio ofreleasable naltrexone to levorphanol is from about 0.278:1 to about2.222:1.

[0077] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is meperidine, wherein the ratio ofreleasable naltrexone to meperidine is from about 0.0037:1 to about0.0296:1.

[0078] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is methadone, wherein the ratio ofreleasable naltrexone to methadone is from about 0.056:1 to about0.444:1.

[0079] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is morphine, wherein the ratio ofreleasable naltrexone to morphine is from about 0.018:1 to about0.148:1.

[0080] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is oxycodone, wherein the ratio ofreleasable naltrexone to oxycodone is from about 0.056:1 to about0.222:1.

[0081] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is codeine, wherein the ratio ofreleasable naltrexone to codeine is from about 0.0083:1 to about0.033:1.

[0082] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is hydromorphone, wherein the ratio ofreleasable naltrexone to hyromorphone is from about 0.222:1 to about0.889:1.

[0083] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is levorphanol, wherein the ratio ofreleasable naltrexone to levorphanol is from about 0.417:1 to about1.667:1.

[0084] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is meperidine, wherein the ratio ofreleasable naltrexone to meperidine is from about 0.0056:1 to about0.022:1.

[0085] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is methadone, wherein the ratio ofreleasable naltrexone to methadone is from about 0.083:1 to about0.333:1.

[0086] In certain embodiments, the releasable opioid antagonist isnaltrexone and the opioid agonist is morphine, wherein the ratio ofreleasable naltrexone to morphine is from about 0.028:1 to about0.111:1.

[0087] In certain embodiments, the releasable antagonist is in an amountto attenuate a side effect of the opioid agonist selected from the groupconsisting of anti-analgesia, hyperalgesia, hyperexcitability, physicaldependence, tolerance, and a combination of any of the foregoing.

[0088] In certain embodiments, the amount of antagonist released duringthe dosing interval enhances the analgesic potency of the opioidagonist.

[0089] In certain embodiments, the amount of the releasable opioidreceptor antagonist is about 100 to about 1000 fold less than the amountof the opioid agonist.

[0090] In certain embodiments, the ratio of the amount of antagonistreleased from the dosage form after tampering to the amount of theantagonist released from the intact dosage form is about 3, 4, 10, 50 or100:1; (w:w) or greater, based on the in-vitro dissolution at 1, 8, 24and/or 36 hours of the dosage form in 900 ml of Simulated Gastric Fluidusing a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C., withor without a switch to Simulated Intestinal Fluid after 1 hour.

[0091] The term “tampering” means any manipulation by mechanical,thermal and/or chemical means which changes the physical properties ofthe dosage form, e.g., to liberate the opioid agonist for immediaterelease if it is in sustained release form, or to make the opioidagonist available for inappropriate use such as administration by analternate route, e.g., parenterally. The tampering can be, e.g., bymeans of crushing, shearing, grinding, chewing, dissolution in asolvent, heating (e.g., greater than about 45° C.), or any combinationthereof.

[0092] The term “at least partially blocking the opioid effect,” isdefined for purposes of the present invention to mean that the opioidantagonist at least significantly blocks the euphoric effect of theopioid agonist, thereby reducing the potential for abuse of the opioidagonist in the dosage form.

[0093] In certain preferred embodiments of the present invention, thesubstantially non-releasable form or non-releasable form of the opioidantagonist comprises opioid antagonist particles in a coating thatsubstantially prevents or prevents the release of the antagonist. Inpreferred embodiments, the coating comprising one or more ofpharmaceutically acceptable hydrophobic material. The coating ispreferably impermeable to the opioid antagonist contained therein and isinsoluble in the gastrointestinal system, thus substantially preventingthe release of the opioid antagonist when the dosage form isadministered orally as intended.

[0094] Accordingly, when the oral dosage form is not tampered with as tocompromise the integrity of the coating, the opioid antagonist containedtherein will not be substantially released during its first hour oftransit through the gastrointestinal system, and thus would not beavailable for absorption. In certain preferred embodiments of thepresent invention, the hydrophobic material comprises a cellulosepolymer or an acrylic polymer that is insoluble in the gastrointestinalfluids and impermeable to the opioid antagonist.

[0095] The term “particles” of opioid antagonist, as used herein, refersto granules, spheroids, beads or pellets comprising the opioidantagonist. In certain preferred embodiments, the opioid antagonistparticles are about 0.2 to about 2 mm in diameter, more preferably about0.5 to about 2 mm in diameter.

[0096] In certain embodiments of the present invention, the releasableantagonist and the non-releasable antagonist can be contained in thesame component. For example, when the opioid antagonist is coated with acoating that substantially prevents its release, and is then mixed withan opioid agonist and compressed into tablets, certain amounts of thecoating might be cracked, thus exposing the opioid antagonist to bereleased upon oral administration. This release can be modified andcontrolled to provide a desired effect as disclosed herein.

[0097] Preferably, the opioid agonist useful for the present inventionmay be selected from the group consisting of morphine, hydromorphone,hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone andmixtures thereof. Preferred examples of the opioid antagonist useful forthe present invention includes naltrexone, naloxone, nalmefene,cyclazacine, levallorphan, pharmaceutically acceptable salts thereof andmixtures thereof.

[0098] In certain embodiments of the present invention, the ratio of theopioid agonist and the opioid antagonist, present in the entireformulation (including releasable and non-releasable form) is about 1:1to about 50:1 by weight, preferably about 1:1 to about 20:1 by weight or15:1 to about 30:1. The weight ratio of the opioid agonist to opioidantagonist, as used in this application, refers to the weight of theactive ingredients. Thus, for example, the weight of the opioidantagonist excludes the weight of the coating or matrix that renders theopioid antagonist substantially non-releasable, or other possibleexcipients associated with the antagonist particles. In certainpreferred embodiments, the ratio is about 1:1 to about 10:1 by weight.Since a portion of the opioid antagonist is in a non-releasable from,the amount of such antagonist within the dosage form may be varied morewidely than the opioid agonist/antagonist combination dosage forms whereboth are available for release upon administration as the formulationdoes not depend on differential metabolism or hepatic clearance forproper functioning. For safety reasons, the amount of the opioidantagonist present in the entire dosage form is selected as not to beharmful to humans even if fully released by tampering with the dosageform.

[0099] In certain preferred embodiments of the present invention, theopioid agonist comprises hydrocodone, oxycodone or pharmaceuticallyacceptable salts thereof and the opioid antagonist, present in asubstantially non-releasable form, comprises naloxone, naltrexone orpharmaceutically acceptable salts thereof.

[0100] The oral dosage form containing an opioid agonist in combinationwith the releasable and non-releasable opioid antagonist includes, butare not limited to, tablets or capsules. The dosage forms of the presentinvention may include any desired pharmaceutical excipients known tothose skilled in the art. The oral dosage forms may further provide animmediate release of the opioid agonist. In certain embodiments, theoral dosage forms of the present invention provide a sustained releaseof the opioid agonist contained therein, or a combination of controlledand immediate release agonist. Such dosage forms of the opioid agonistmay be prepared in accordance with formulations/methods of manufactureknown to those skilled in the art of pharmaceutical formulation.

[0101] The benefits of the abuse-resistant dosage form are especiallygreat in connection with oral dosage forms of strong opioid agonists(e.g., oxycodone or hydrocodone), which provide valuable analgesics butcan be the subject of abuse. This is particularly true for sustainedrelease opioid agonist products which have a large dose of a desirableopioid agonist intended to be released over a period of time in eachdosage unit. Drug abusers take such sustained-release product and crush,grind, extract or otherwise damage the product so that the full contentsof the dosage form become available for immediate absorption. Since suchtampering of the dosage form of the invention results in opioidantagonist (in addition to the releasable antagonist) also becomingavailable for absorption, the present invention provides a means forfrustrating such abuse. In addition, the present invention addresses therisk of overdose to ordinary patients from “dumping” effect of the fulldose of the opioid agonist if the product is accidentally chewed orcrushed.

[0102] The term “sustained release” is defined for purposes of thepresent invention as the release of the opioid agonist from the oraldosage form at such a rate that blood (e.g., plasma) concentrations(levels) are maintained within the therapeutic range (above the minimumeffective analgesic concentration or “MEAC”) but below toxic levels overa period of 8 to 24 hours, preferable over a period of time indicativeof a twice-a-day or a once-a-day formulation.

[0103] The invention may provide for a safer product (e.g., lessrespiratory depression), if the product is misused, as well as one withless risk of abuse.

[0104] In certain embodiments, a combination of two opioid agonists isincluded in the formulation. In further embodiments, one or more opioidagonist is included and a further non-opioid drug is also included. Suchnon-opioid drugs would preferably provide additional analgesia, andinclude, for example, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs (“NSAIDS”), NMDA antagonists, andcycooxygenase-II inhibitors (“COX-II inhibitors”).

[0105] In yet further embodiments, a non-opioid drug can be includedwhich provides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, or antihistamine drugs, and the like.

[0106] For purposes of the present invention, the term “opioid agonist”is interchangeable with the term “opioid” or “opioid analgesic” andshall include combinations of more than one opioid agonist, and alsoinclude the base of the opioid, mixed agonist-antagonists, partialagonists, pharmaceutically acceptable salts thereof, stereoisomersthereof, ethers and esters thereof, and mixtures thereof.

[0107] For purposes of the present invention, the term “opioidantagonist” shall include combinations of more than one opioidantagonist, and also include the base, pharmaceutically acceptable saltsthereof, stereoisomers thereof, ethers and esters thereof, and mixturesthereof.

[0108] The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed opioidagonists and antagonists. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,secium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

[0109] Some of the opioid agonists and antagonists disclosed herein maycontain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms. The presentinvention is also meant to encompass all such possible forms as well astheir racemic and resolved forms and mixtures thereof. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well.

[0110] As used herein, the term “stereoisomers” is a general term forall isomers of individual molecules that differ only in the orientationof their atoms is space. It includes enantiomers and isomers ofcompounds with more than one chiral center that are not mirror images ofone another (diastereomers).

[0111] The term “chiral center” refers to a carbon atom to which fourdifferent groups are attached.

[0112] The term “enantiomer” or “enantiomeric” refers to a molecule thatis nonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

[0113] The term “racemic” refers to a mixture of equal parts ofenantiomers and which is optically inactive.

[0114] The term “resolution” refers to the separation or concentrationor depletion of one of the two enantiomeric forms of a molecule.

[0115] The present invention is further directed to a method ofdecreasing the potential for abuse of an opioid agonist in an oraldosage form. The method comprises providing the opioid agonist in anoral dosage form as described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0116] It has been postulated that there exists at least threesubspecies of opioid receptors, designated mu, kappa, and delta. Withinthis framework, the mu receptor is considered to be involved in theproduction of superspinal analgesia, respiratory depression, euphoria,and physical dependence. The kappa receptor is considered to be involvedin inducing spinal analgesia, miosis and sedation. Activation of thegamma receptors causes dysphoria and hallucinations, as well asrespiratory and vasomotor stimulatory effects. A receptor distinct fromthe mu receptor and designated gamma has been described in the mouse vasdeferens, Lord, et al. Nature, 1977, 267,495-99. Opioid agonists arethought to exert their agonist actions primarily at the mu receptor andto a lesser degree at the kappa receptor. There are a few drugs thatappear to act as partial agonists at one receptor type or another. Suchdrugs exhibit a ceiling effect. Such drugs include nalorphine, propiram,and buprenorphine. Still other drugs act as competitive antagonists atthe mu receptor and block the effects of morphine-like drugs, byexerting their actions at the kappa and omega receptors. The termagonist-antagonist has evolved to describe such mechanism of actions.

[0117] The present invention is directed to a controlled release opioidanalgesic, similar in analgesic spectrum to existing controlled-releaseopioid analgesics, which is formulated in order to reduce and minimize,misuse, abuse and diversion. In certain embodiments, thesecharacteristics are conferred by the inclusion of an opioid antagonistsuch as naltrexone HCl, which is itself formulated in a uniquecontrolled release matrix. The properties of this formulation aredeveloped to liberate the antagonist in conditions of misuse ortampering yet a negligible amount of antagonist would be released (anamount which does not affect the analgesia experienced by the patient)under the prescribed conditions of use.

[0118] In certain embodiments of the invention, the release for theantagonist component of the formulation is expressed in terms of a ratioof the release achieved after tampering, e.g., by crushing or chewing,relative to the amount released from the intact formulation. The ratiois therefore expressed as [Crushed]/[Whole], and it is desired that thisratio have a numerical range of at least 3:1 or greater (crushed releasein 1 hour/intact release in 1hour).

[0119] In certain preferred embodiments, the opioid antagonist in asubstantially non-releasable form comprises opioid antagonist particlescoated with a coating that substantially prevents its release. Inpreferred embodiments, such coating surrounds the antagonist particlesand is impermeable to the drug and is insoluble in the gastrointestinalsystem. When the dosage form of the present invention is orallyadministered to humans, the opioid antagonist is not substantiallyreleased from the coating and is, therefore, not available forabsorption into the body. Thus, the opioid antagonist, although presentin the dosage form, does not substantially block the analgesiceffectiveness of the opioid agonist. However, if the oral dosage form ofthe present invention is tampered with as to compromise the integrity ofthe coating, the opioid antagonist contained therein would be madeavailable to at least partially block the effect of the opioid agonist.This characteristic decreases the potential for abuse or diversion ofthe opioid agonist in the oral dosage form. For example, if one attemptsto abuse the drug contained in the oral dosage form of the presentinvention by, e.g., chewing, crushing, grinding or dissolving it in asolvent with heat (e.g., greater than about 45° C. to about 50° C.), thecoating will be damaged and will no longer prevent the opioid antagonistfrom being released. Upon administration, the opioid antagonist will bereleased and significantly block the euphoric effect of the opioidagonist.

[0120] In certain embodiments of the invention, the ratio of the opioidagonist to the coated opioid antagonist is such that when the oraldosage form is tampered with as to compromise the integrity of thecoating that renders the opioid antagonist substantially non-releasable,the euphoric effect of the agonist would be negated by the opioidantagonist when misused by a human subject orally, parenterally,intranasally or sublingually. In certain preferred embodiments of theinvention, the euphoric effect of the opioid agonist would be negated bythe opioid antagonist when misused parenterally or sublingually.

[0121] In certain other embodiments of the present invention, the opioidantagonist in a substantially non-releasable form comprises an opioidantagonist dispersed in a matrix that renders the antagonistsubstantially non-releasable, wherein the matrix comprises one or moreof a pharmaceutically acceptable hydrophobic material. The antagonist issubstantially not released from the matrix, thus is not made availableto be absorbed during its transit through the gastrointestinal system.

[0122] In certain other embodiments of the present invention, the opioidantagonist in a matrix that renders the antagonist substantiallynon-releasable comprises an opioid antagonist dispersed in amelt-extruded matrix, wherein the matrix comprises one or more or apharmaceutically acceptable hydrophobic material.

[0123] All discussion herein directed to the non-releasable componentand its release upon tampering as well as all general discussion is inaddition to the releasable antagonist of the intact dosage form. Asdiscussed, the releasable form of the antagonist can be released fromthe same component as the non-releasable, from a separate component orfrom a combination of both components.

[0124] The releasable antagonist of the present invention can comprisesan amount of the opioid antagonist such as naltrexone in an amount (i)which does not cause a reduction in the level of analgesia elicited fromthe dosage form upon oral administration to a non-therapeutic level and(ii) which provides at least a mildly negative, “aversive” experience inphysically dependent human subjects, for example, physically dependentaddicts (e.g., precipitated abstinence syndrome) when taking one dosageform or more than one dosage form. Preferably, the amount of antagonistincluded in the intact oral dosage form is (iii) less positivelyreinforcing (e.g., less “liked”) by a non-physically dependent humansubject, e.g., opioid addict, than a comparable oral dosage form withoutthe antagonist included.

[0125] The amount of antagonist which is useful to achieve parameters(i)-(iii) set forth in the preceding paragraph may be determined atleast in part, for example, through the use of “surrogate” tests, suchas a VAS scale (where the subject grades his/her perception of theeffect of the dosage form) and/or via a measurement such as pupil size(measured by pupillometry). Such measurements allow one skilled in theart to determine the dose of antagonist relative to the dose of agonistwhich causes a diminution in the opiate effects of the agonist.Subsequently, one skilled in the art can determine the level of opioidantagonist that causes aversive effects in physically dependent subjectsas well as the level of opioid antagonist that minimizes “liking scores”or opioid reinforcing properties in non-physically dependent addicts.Once these levels of opioid antagonist are determined, it is thenpossible to determine the range of antagonist dosages at or below thislevel which would be useful in achieving parameters (i)-(iii) set forthin the preceding paragraph.

[0126] In certain preferred embodiments, the opioid agonist or analgesicis selected from the group consisting of hydrocodone, morphine,hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone,or salts thereof, or mixtures thereof. In certain preferred embodiments,the opioid agonist is hydrocodone or oxycodone. Equianalgesic doses ofthese opioids, in comparision to a 15 mg dose of hydrocodone, are setforth in Table 1 below: TABLE 1 Equianalgesic Doses of Opioids OpioidCalculated Dose (mg) Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0Hydromorphone 3.375 Levorphanol 1.8 Meperidine 135.0 Methadone 9.0Morphine 27.0

[0127] Based on a ratio of releasable naltrexone in an amount from about0.5 to about 4 mg per 15 mg of hydrocodone, the approximate ratio ofnaltrexone to 1 mg of each opioid is set forth in Table 2: TABLE 2Weight Ratio of Naltrexone per Dose Opioid Weight Ratio Naltrexone perOpioid 1 mg Opioid Oxycodone 0.037 to 0.296 Codeine 0.005 to 0.044Hydrocodone 0.033 to 0.267 Hydromorphone 0.148 to 1.185 Levorphanol0.278 to 2.222 Meperidine 0.0037 to 0.0296 Methadone 0.056 to 0.444Morphine 0.018 to 0.148

[0128] Based on a ratio of about 0.75 mg to about 3 mg naltrexone per 15mg hydrocodone of naltrexone, the approximate ratio of naltrexone to 1mg of each opioid is set forth in Table 3: TABLE 3 Weight Ratio ofNaltrexone per Dose Opioid Opioid Weight Ratio Naltrexone Oxycodone0.056 to 0.222 Codeine 0.0083 to 0.033  Hydrocodone 0.050 to 0.200Hydromorphone 0.222 to 0.889 Levorphanol 0.417 to 1.667 Meperidine0.0056 to 0.022  Methadone 0.083 to 0.333 Morphine 0.028 to 0.111

[0129] Ratios of opioids to other antagonists besides naltrexone can beobtained by comparing equivalent doses of other antagonists to equaldoses of naltrexone. The specification and examples of PCT/US98/27257which disloses releasable opioid antagonist/agonist formulations ishereby incorporated by reference in combination with the sequesteredantagonist as disclosed herein.

[0130] The releasable antagonist of the present invention can comprisesan amount of the opioid antagonist which can selectively enhancing thepotency of the opioid agonists and simultaneously attenuatingundesirable side-effects, including physical dependence, caused by thechronic administration of said opioid agonists. Morphine and otherbimodally-acting (inhibitory/excitatory) opioid agonists bind to andactivate inhibitory and excitatory opioid receptors on nociceptiveneurons mediating pain. Activation of inhibitory receptors by saidagonists causes analgesia. Activation of excitatory receptors by saidagonists results in anti-analgesic effects, development of physicaldependence, tolerance, hyperexcitability, hyperalgesia and otherundesirable side-effects. The co-administration of the releasable opioidantagonist which binds to and inactivates excitatory opioid receptorsresults in the blocking of excitatory anti-analgesic side-effects ofsaid opioid agonists on these neurons, thereby resulting in enhancedanalgesic potency which permits the use of lower doses of morphine orother conventional opioid analgesics. The specification and examples ofU.S. Pat. No. 5,472,943 which describes such formulations and methods ishereby incorporated by reference in combination with the sequesteredantagonist as disclosed herein.

[0131] All known references of releasable opioid antagonists with opioidagonists such as U.S. Pat. No. 3,773,955 (Pachter, et al.); U.S. Pat.No. 3,493,657 (Lewenstein, et al.) U.S. Pat. No. 4,457,933 (Gordon, etal.); U.S. Pat. No. 4,582,835 (Lewis) U.S. Pat. Nos. 5,512,578;5,472,943; 5,580,876; and 5,767,125 (Crain) and U.S. Pat. Nos. 4,769,372and 4,785,000 (Kreek) can be combined with a sequestered antagonist asdisclosed herein and all of these references are hereby incoporated byreference.

[0132] U.S. Provisional Application Nos. 60/181,369 and 60/181,358 bothfiled Feb. 6, 2000 are hereby incorporated by reference in combinationwith the three component invention as disclosed herein.

[0133] All commercial products of opioid agonist and releasableantagonists can be combined with a sequestered antagonist as disclosedherein. For example, Talwin NX can be formulated with a sequesteredantagonist to reduce oral abuse as well as parenteral abuse of theopioid therein.

[0134] In preferred embodiments, opioid agonists useful in the presentinvention include, but are not limited to, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl andderivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narcine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium,oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sufentanil,tilidine, tramadol, mixtures of any of the foregoing, salts of any ofthe foregoing, and the like. In certain embodiments, the amount of theopioid agonist in the claimed opioid composition may be about 75 ng to750 mg.

[0135] Although hydrocodone and oxycodone are effective in themanagement of pain, there has been an increase in their abuse byindividuals who are psychologically dependent on opioids or who misuseopioids for non-therapeutic reasons. Previous experience with otheropioids has demonstrated a decreased abuse potential when opioids areadministered in combination with a narcotic antagonist especially inpatients who are ex-addicts. Weinhold L L, et al. Buprenorphine Aloneand in Combination with Naltrexone in Non-Dependent Humans, Drug andAlcohol Dependence 1992; 30:263-274; Mendelson J., et al., Buprenorphineand Naloxone Interactions in Opiate-Dependent Volunteers, Clin PharmTher. 1996; 60:105-114; both of which are hereby incorporated byreference. These combinations, however, do not contain the opioidantagonist that is in a substantially non-releasable form. Rather, theopioid antagonist is released in the gastrointestinal system when orallyadministered and is made available for absorption, relying on thephysiology of the host to differentially metabolize the agonist andantagonist and negate the agonist effects.

[0136] Hydrocodone is a semisynthetic narcotic analgesic and antitussivewith multiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

[0137] Oral hydrocodone is also available in Europe (Belgium, Germany,Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussiveagent. A parenteral formulation is also available in Germany as anantitussive agent. For use as an analgesic, hydrocodone bitartrate iscommercially available in the United States only as a fixed combinationwith non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.)for relief of moderate or moderately severe pain.

[0138] A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of an opioid antagonist inreleasable and non-releasable form.

[0139] Oxycodone, chemically known as4,5-expoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

[0140] Oxycodone is commercially available in the United States, e.g.,as Oxycontin® from Purdue Pharma L.P. as controlled-release tablets fororal administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodonehydrochloride, and as OxyIR™ also from Purdue Pharma L.P., asimmediate-release capsules containing 5 mg oxycodone hydrochloride. Thepresent invention is contemplated to encompass all such formulations,with the inclusion of an opioid antagonist in a substantiallynon-releasable form.

[0141] In preferred embodiments, the opioid antagonist of the presentinvention includes naltrexone, nalmefene, cyclazacine, levallorphan andmixtures thereof. In certain preferred embodiments, the opioidantagonist is naloxone or naltrexone. In certain embodiments, the amountof the opioid antagonist, present in a substantially non-releasableform, may be about 10 ng to 275 mg.

[0142] Naloxone is an opioid antagonist which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to havesignificantly lower potency than as when parenterally administered. Oraldosage of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed. Weinberg, et al.,Sublingual Absorption of selected Opioid Analgesics, Clin PharmacolTher. (1988); 44:335-340.

[0143] Other opioid antagonists, for example, cyclazocine andnaltrexone, both of which have cyclopropylmethyl substitutions on thenitrogen, retain much of their efficacy by the oral route and theirdurations of action are much longer, approaching 24 hours after oraldoses.

[0144] In the treatment of patients previously addicted to opioids,naltrexone has been used in large oral doses (over 100 mg) to preventeuphorigenic effects of opioid agonists. Naltrexone has been reported toexert strong preferential blocking action against mu over delta sites.Naltrexone is known as a synthetic congener of oxymorphone with noopioid agonist properties, and differs in structure from oxymorphone bythe replacement of the methyl group located on the nitrogen atom ofoxymorphone with a cyclopropylmethyl group. The hydrochloride salt ofnaltrexone is soluble in water up to about 100 mg/cc. Thepharmacological and pharmacokinetic properties of naltrexone have beenevaluated in multiple animal and clinical studies. See, e.g., Gonzalez JP, et al. Naltrexone: A review of its Pharmacodynamic andPharmacokinetic Properties and Therapeutic Efficacy in the Management ofOpioid Dependence. Drugs 1988; 35:192-213, hereby incorporated byreference. Following oral administration, naltrexone is rapidly absorbed(within 1 hour) and has an oral bioavailability ranging from 5-40%.Naltrexone's protein binding is approximately 21% and the volume ofdistribution following single-dose administration is 16.1 L/kg.

[0145] Naltrexone is commercially available in tablet form (Revia®,DuPont) for the treatment of alcohol dependence and for the blockade ofexogenously administered opioids. See, e.g., Revia (naltrexonehydrochloride tablets). Physician's Desk Reference 51^(st) ed.,Montvale, N.J. “Medical Economics” 1997; 51:957-959. A dosage of 50 mgRevia® blocks the pharmacological effects of 25 mg IV administeredheroin for up to 24 hours.

[0146] It is known that when coadministered with morphine, heroin orother opioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with narcotic addicts having good prognosis, as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

[0147] In certain embodiments of the present invention, ratio of theopioid agonist to the substantially non-releasable form of an opioidantagonist in the oral dosage form is such that the effect of the opioidagonist is at least partially blocked when the dosage form is chewed,crushed or dissolved in a solvent and heated, and administered orally,intranasally, parenterally or sublingually. Since the oral dosage formof the present invention, when administered properly as intended, wouldnot substantially release the opioid antagonist, the amount of suchantagonist may be varied more widely than if the opioid antagonist isavailable to be released into the gastrointestinal system upon oraladministration. For safety reasons, the amount of the antagonist presentin a substantially non-releasable form should not be harmful to humanseven if fully released. The ratio of particular opioid agonist toantagonist can be determined without undue experimentation by oneskilled in the art.

[0148] The oral dosage form of the present invention may furtherinclude, in addition to an opioid agonist and releasable andnon-releasable antagonist, one or more drugs that may or may not actsynergistically therewith. Thus, in certain embodiments, a combinationof two opioid agonists may be included in the dosage form, in additionto the opioid antagonist. For example, the dosage form may include twoopioid agonists having different properties, such as half-life,solubility, potency, and a combination of any of the foregoing. In yetfurther embodiments, one or more opioid agonist is included and afurther non-opioid drug is also included, in addition to the opioidantagonist. Such non-opioid drugs would preferably provide additionalanalgesia, and include, for example, aspirin, acetaminophen;non-steroidal anti-inflammatory drugs (“NSAIDS”), e.g., ibuprofen,ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists,e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine;cycooxygenase-II inhibitors (“COX-II inhibitors”); and/or glycinereceptor antagonists.

[0149] In certain preferred embodiments of the present invention, theinvention allows for the use of lower doses of the opioid analgesic byvirtue of the inclusion of an additional non-opioid agonist, such as anNSAID or a COX-2 inhibitor. By using lower amounts of either or bothdrugs, the side effects associated with effective pain management inhumans are reduced.

[0150] Suitable non-steroidal anti-inflammatory agents, includingibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Useful dosages of these drugs arewell known to those skilled in the art.

[0151] N-methyl-D-aspartate (NMDA) receptor antagonists are well knownin the art, and encompass, for example, morphinans such asdextromethorphan or dextrorphan, ketamine, d-methadone orpharmaceutically acceptable salts thereof. For purposes of the presentinvention, the term “NMDA antagonist” is also deemed to encompass drugsthat block a major intracellular consequence of NMDA-receptoractivation, e.g. a ganglioside such as GM₁ or GT_(1b) a phenothiazinesuch as trifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et. al. patents.

[0152] The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.), hereby incorporated by reference.

[0153] COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,474,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day are therapeuticallyeffective in combination with an opioid analgesic. Alternatively, about0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in combination with an opioid analgesic.

[0154] In yet further embodiments, a non-opioid drug can be includedwhich provides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

PREPARATION OF OPIOID ANTAGONIST IN A SUBSTANTIALLY NON-RELEASABLE ORNON-RELEASABLE FORM

[0155] In certain embodiments of the present invention, an opioidantagonist in a substantially non-releasable form may be prepared bycombining the antagonist with one or more of a pharmaceuticallyacceptable hydrophobic material. For example, opioid antagonistparticles may be coated with coating that substantially prevents therelease of the antagonist, the coating comprising the hydrophobicmaterials(s). Another example would be an opioid antagonist that isdispersed in a matrix that renders the antagonist to be substantiallynon-releasable, the matrix comprising the hydrophobic materials(s). Incertain embodiments, the pharmaceutical acceptable hydrophobic materialcomprises a cellulose polymer selected from the group consisting ofethylcellulose, cellulose acetate, cellulose propionate (lower, mediumor higher molecular weight), cellulose acetate propionate, celluloseacetate butyrate, cellulose acetate phthalate and cellulose triacetate.An example of ethylcellulose is one that has an ethoxy content of 44 to55%. Ethylcellulose may be used in the form of an alcoholic solution. Incertain other embodiments, the hydrophobic material comprises polylacticacid, polyglycolic acid or a co-polymer of the polylactic andpolyglycolic acid.

[0156] In certain embodiments, the hydrophobic material may comprise acellulose polymer selected from the group consisting of cellulose ether,cellulose ester, cellulose ester ether, and cellulose. The cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than zero and up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups present onthe anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials include apolymer selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di, and tricellulose alkanylates,moni, di, and tricellulose aroylates, and mono, di, and tricellulosealkenylates. Exemplary polymers include cellulose acetate having a D.S.and an acetyl content up to 21%; cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2 to3 and an acetyl content of 35 to 44.8%.

[0157] More specific cellulosic polymers include cellulose propionatehaving a D.S. of 1.8 and a propyl content of 39.2 to 45 and a hydroxylcontent of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8,an acetyl content of 13 to 15% and a butyryl content of 34 to 39%;cellulose acetate butyrate having an acetyl content of 2 to 29%, abutyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%;cellulose triacylate having a D.S. of 2.9 to 3 such as cellulosetriacetate, cellulose trivalerate, cellulose trilaurate, cellulosetripatmitate, cellulose trisuccinate, and cellulose trioctanoate;cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedipentanoate, and coesters of cellulose such as cellulose acetatebutyrate, cellulose acetate octanoate butyrate and cellulose acetatepropionate.

[0158] Additional cellulose polymers useful for preparing an opioidantagonist in a substantially non-releasable form includes acetaldehydedimethyl cellulose acetate, cellulose acetate ethylcarbamate, celluloseacetate methylcarbamate, and cellulose acetate dimethylaminocelluloseacetate.

[0159] An acrylic polymer useful for preparation of the opioidantagonist in a substantially non-releasable form includes, but are notlimited to, acrylic resins comprising copolymers synthesized fromacrylic and methacrylic acid esters (e.g., the copolymer of acrylic acidlower alkyl ester and methacrylic acid lower alkyl ester) containingabout 0.02 to 0.03 mole of a tri (lower alkyl) ammonium group per moleof the acrylic and methacrylic monomers used. An example of a suitableacrylic resin is a polymer manufactured by Rohm Pharma GmbH and soldunder the Eudragit® RS trademark. Eudragit RS30D is preferred. Eudragit®RS is a water insoluble copolymer of ethyl acrylate (EA), methylmethacrylate (MM) and trimethylammoniumethyl methacrylate chloride (TAM)in which the molar ratio of TAM to the remaining components (EA and MM)is 1:40. Acrylic resins such as Eudragit® RS may be used in the form ofan aqueous suspension.

[0160] In certain embodiments of the invention, the acrylic polymer maybe selected from the group consisting of acrylic acid and methacrylicacid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate co-polymer.

[0161] When the opioid antagonist in a substantially non-releasable formcomprises opioid antagonist particles coated with a coating that rendersthe antagonist substantially non-releasable, and when a cellulosepolymer or an acrylic polymer is used for preparation of the coatingcomposition, suitable plasticizers, e.g., acetyl triethyl citrate and/oracetyl tributyl citrate may also be admixed with the polymer. Thecoating may also contain additives such as coloring agents, talc and/ormagnesium stearate, which are well known in the coating art.

[0162] The coating composition may be applied onto the opioid antagonistparticles by spraying it onto the particles using any suitable sprayequipment known in the part. For example, a Wuster fluidized-bed systemmay be used in which an air jet, injected from underneath, fluidizes thecoated material and effects drying while the insoluble polymer coatingis sprayed on. The thickness of the coating will depend on thecharacteristics of the particular coating composition being used.However, it is-well within the ability of one skilled in the art todetermine by routine experimentation the optimum thickness of aparticular coating required for a particular dosage form of the presentinvention.

[0163] The pharmaceutically acceptable hydrophobic material useful forpreparing an opioid antagonist in a substantially non-releasable formincludes a biodegradable polymer comprising a poly(lactic/glycolic acid)(“PLGA”), a polylactide, a polyglycolide, a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, polyesthers, polydioxanone, polygluconate,polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyphosphoesther or mixtures or blends of any of these.

[0164] In certain embodiments, biodegradable polymer comprises apoly(lactic/glycolic acid), a copolymer of lactic and glycolic acid,having molecular weight of about 2,000 to about 500,000 daltons. Theratio of lactic acid to glycolic acid is from about 100:0 to about25:75, with the ratio of lactic acid to glycolic acid of 65:35 beingpreferred.

[0165] Poly(lactic/glycolic acid) may be prepared by the procedure setforth in U.S. Pat. No. 4,293,539 (Ludwig et al.), the disclosure ofwhich is hereby incorporated by reference in its entirety. In brief,Ludwig prepares the copolymer by condensation of lactic acid andglycolic acid in the presence of a readily removable polymerizationcatalyst (e.g., a strong acid ion-exchange resin such as DowexHCR-W2-H). The amount of catalyst is not critical to the polymerization,but typically is from about 0.01 to about 20 parts by weight relative tothe total weight of combined lactic acid and glycolic acid. Thepolymerization reaction may be conducted without solvents at atemperature from about 100 C. to about 250 C. for about 48 to about 96hours, preferably under a reduced pressure to facilitate removal ofwater and by-products. Poly(lactic/glycolic acid) is then recovered byfiltering the molten reaction mixture in an organic solvent such asdichloromethane or acetone and then filtering to remove the catalyst.

[0166] Once the opioid antagonist in a substantially non-releasable formis prepared, it may be combined with an opioid agonist and releasableantagonist, along with conventional excipients known in the art, toprepare the oral dosage form of the present invention.

[0167] In certain preferred embodiments of the invention, the oraldosage form is a capsule or a tablet. When being formulated as a tablet,the agents may be combined with one or more inert, non-toxicpharmaceutical excipients which are suitable for the manufacture oftablets. Such excipients include, for example, an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate.

[0168] The oral dosage form of the present invention may be formulatedto provide immediate release of the opioid agonist contained therein. Inother embodiments of the invention, however, the oral dosage formprovides sustained-release of the opioid agonist.

[0169] In certain embodiments, the oral dosage forms providing sustainedrelease of the opioid agonist and/or releasable antagonist may beprepared by admixing the opioid antagonist in a substantiallynon-releasable form with the agonist and releasable antagonist anddesirable pharmaceutical excipients to provide a tablet, and thencoating the tablet with a sustained-release tablet coating.

[0170] In certain embodiments of the invention, sustained release opioidagonist tablets may be prepared by admixing the substantiallynon-releasable form of an opioid antagonist with a releasable opioidantagonist and agonist in a matrix that provides the tablets withsustained-releasing properties.

[0171] Detailed description for preparing sustained-release oral dosageforms according to the present invention is set forth below.

PREPARATION OF CONTROLLED RELEASE DOSAGE FORMS CONTAINING AN OPIOIDAGONIST AND A SUBSTANTIALLY NON-RELEASABLE FORM OF AN OPIOID ANTAGONIST

[0172] A combination of the opioid agonist and a substantiallynon-releasable form of an opioid antagonist may be formulated as acontrolled or sustained release oral formulation in any suitable tablet,coated tablet or multiparticulate formulation known to those skilled inthe art. The sustained release dosage form may optionally include asustained release carrier which is incorporated into a matrix along withthe opioid agonist and a non-available form of an opioid antagonist, ormay be applied as a sustained release coating.

[0173] In embodiments in which the opioid agonist comprises hydrocodone,the sustained release oral dosage forms may include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. In sustainedrelease oral dosage forms where hydromorphone is the therapeuticallyactive opioid, it is included in an amount from about 2 mg to about 64mg hydromorphone hydrochloride. In another embodiment, the opioidagonist comprises morphine, and the sustained release oral dosage formsof the present invention include from about 2.5 mg to about 800 mgmorphine, by weight. In yet another embodiment, the opioid agonistcomprises oxycodone and the sustained release oral dosage forms includefrom about 2.5 mg to about 800 mg oxycodone. In certain preferredembodiments, the sustained release oral dosage forms include from about20 mg to about 30 mg oxycodone. Controlled release oxycodoneformulations are known in the art. The following documents describevarious controlled release oxycodone formulations suitable for use inthe invention described herein, and processes for their manufacture:U.S. Pat. Nos. 5,266,331; 5,549,912; 5,508,042; and 5,656,295. Theopioid agonist may comprise tramadol and the sustained release oraldosage forms may include from about 25 mg to 800 mg tramadol per dosageunit. The dosage form may contain more than one opioid agonist toprovide a substantially equivalent therapeutic effect. Alternatively,the dosage form may contain molar equivalent amounts of other salts ofthe opioid agonists useful in the present invention.

[0174] In one preferred embodiment of the present invention, thesustained release dosage form comprises such particles comprising theopioid agonist, wherein the particles have diameter from about 0.1 mm toabout 2.5 mm, preferably from about 0.5 mm to about 2 mm.

[0175] The opioid agonist particles are preferably film coated with amaterial that permits release of the opioid agonist at a sustained ratein an aqueous medium. The film coat is chosen so as to achieve, incombination with the other stated properties, a desired in-vitro releaserate. The sustained release coating formulations of the presentinvention should be capable of producing a strong, continuous film thatis smooth and elegant, capable of supporting pigments and other coatingadditives, non-toxic, inert, and tack-free.

[0176] The dosage forms comprising an opioid agonist and a substantiallynon-releasable opioid antagonist may optionally be coated with one ormore materials suitable for the regulation of the opioid agonist releaseor for the protection of the formulation. In one embodiment, coatingsare provided to permit either pH-dependent or pH-independent release,e.g., when exposed to gastrointestinal fluid. A pH-dependent coatingserves to release the opioid in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine, such that anabsorption profile is provided which is capable of providing at leastabout eight hours and preferably about twelve hours to up to abouttwenty-four hours of analgesia to a patient. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseof the opioid regardless of pH-changes in the environmental fluid. e.g.,the GI tract. It is also possible to formulate compositions whichrelease a portion of the dose in one desired area of the GI tract, e.g.,the stomach, and release the remainder of the dose in another area ofthe GI tract, e.g., the small intestine.

[0177] Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointostinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

[0178] In certain preferred embodiments, the substrate (e.g., tabletcore bead, matrix particle) containing the opioid analgesic (with orwithout the COX-2 inhibitor) is coated with a hydrophobic materialselected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii)mixtures thereof. The coating may be applied in the form of an organicor aqueous solution or dispersion. The coating may be applied to obtaina weight gain from about 2 to about 25% of the substrate in order toobtain a desired sustained release profile. Coatings derived fromaqueous dispersions are described, e.g., in detail in U.S. Pat. Nos.5,273,760 and 5,286,493, assigned to the Assignee of the presentinvention and hereby incorporated by reference.

[0179] Other examples of sustained release formulations and coatingswhich may be used in accordance with the present invention includeAssignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, herebyincorporated by reference in their entirety.

ALKYLCELLULOSE POLYMERS

[0180] Cellulosic materials and polymers, including alkylcelluloses,provide hydrophobic materials well suited for coating the beadsaccording to the invention. Simply by way of example, one preferredalkylcellulosic polymer is ethylcellulose, although the artisan willappreciate that other cellulose and/or alkylcellulose polymers may bereadily employed, singly or in any combination, as all or part of ahydrophobic coating according to the invention.

[0181] One commercially-available aqueous dispersion of ethylcelluloseis Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® isprepared by dissolving the ethylcellulose in a water-immiscible organicsolvent and then emulsifying the same in water in the presence of asurfactant and a stabilizer. After homogenization to generate submicrondroplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatexduring the manufacturing phase. Thus, prior to using the same as acoating, it is necessary to intimately mix the Aquacoat® with a suitableplasticizer prior to use.

[0182] Another aqueous dispersion of ethylcellulose is commerciallyavailable as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). Thisproduct is prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(dibutyl sebacate), and stabilizer (oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly ontosubstrates.

ACRYLIC POLYMERS

[0183] In other preferred embodiments of the present invention, thehydrophobic material comprising the controlled release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

[0184] In certain preferred embodiments, the acrylic polymer iscomprised of one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers are well known in the art, and are described inNF XVII as fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups.

[0185] In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth)acrylic esters.

[0186] Certain methacrylic acid ester-type polymers are useful forpreparing pH-dependent coatings which may be used in accordance with thepresent invention. For example, there are a family of copolymerssynthesized from diethylaminoethyl methacrylate and other neutralmethacrylic esters, also known as methacrylic acid copolymer orpolymeric methacrylates, commercially available as Eudragit® from RöhmTech, Inc. There are several different types of Eudragit®. For example,Eudragit® E is an example of a methacrylic acid copolymer which swellsand dissolves in acidic media. Eudragit® L is a methacrylic acidcopolymer which does not swell at about pH<5.7 and is soluble at aboutpH>6. Eudragit® S does not swell at about pH<6.5 and is soluble at aboutpH>7. Eudragit® RL and Eudragit® RS are water swellable, and the amountof water absorbed by these polymers is pH-dependent, however, dosageforms coated with Eudragit® RL and RS are pH-independent.

[0187] In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same ate swellable and permeable in aqueous solutions anddigestive fluids.

[0188] The Eudragit® RL/RS dispersions of the present invention may bemixed together in any desired ratio in order to ultimately obtain asustained release formulation having a desirable dissolution profile.Desirable sustained release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

PLASTICIZERS

[0189] In embodiments of the present invention where the coatingcomprises an aqueous dispersion of a hydrophobic material, the inclusionof an effective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physcial properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

[0190] Examples of suitable plasticizers for ethylcellulose includewater insoluble plasticizers such as dibutyl sebacate, diethylphthalate, triethyl citrate, tributyl citrate, and triacetin, althoughit is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may beused. Triethyl citrate is an especially preferred plasticizer for theaqueous dispersions of ethyl cellulose of the present invention.

[0191] Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

[0192] It has further been found that the addition of a small amount oftalc reduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

PROCESSES FOR PREPARING COATED BEADS

[0193] When a hydrophobic controlled release coating material is used tocoat inert pharmaceutical beads such as nu pariel 18/20 beads, which arealready coated with an opioid agonist, a plurality of the resultantsolid controlled release beads may thereafter be placed in a gelatincapsule, with the opioid antagonist in a substantially non-releasableform. The dosage form provides an effective controlled release dose ofthe opioid agonist when ingested and contacted by an environmentalfluid, e.g., gastric fluid or dissolution media.

[0194] The controlled release bead formulations of the present inventionslowly release the opioid agonist, e.g., when ingested and exposed togastric fluids, and then to intestinal fluids. The controlled releaseprofile of the formulations of the invention can be altered, forexample, by varying the amount of overcoating with the hydrophobicmaterial, altering the manner in which the plasticizer is added to thehydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc. The dissolutionprofile of the ultimate product may also be modified, for example, byincreasing or decreasing the thickness of the retardant coating.

[0195] Spheroids or beads coated with an opioid agonist may be prepared,e.g., by dissolving the drug in water and then spraying the solutiononto a substrate, for example, nu pariel 18/20 beads, using a Wusterinsert. Optionally, additional ingredients are also added prior tocoating the beads in order to assist the binding of the opioid to thebeads, and/or to color the solution, etc. For example, a product whichincludes hydroxypropylmethylcellulose, etc. with or without colorant(e.g., Opadry®, commercially available from Colorcon, Inc.) may be addedto the solution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the therapeutically active agent from the hydrophobiccontrolled release coating. An example of a suitable barrier agent isone which comprises hydroxypropylmethylcellulose. However, anyfilm-former known in the art may be used. It is preferred that thebarrier agent does not affect the dissolution rate of the final product.

[0196] The beads may then be overcoated with an aqueous dispersion ofthe hydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat ® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

[0197] The coating solutions of the present invention preferablycontain, in addition to the film-former, plasticizer, and solvent system(i.e., water), a colorant to provide elegance and product distinction.Color may be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

[0198] Plasticized hydrophobic material may be applied onto thesubstrate comprising the therapeutically active agent by spraying usingany suitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid therapeutically active agent when the coated substrate is exposedto aqueous solutions, e.g. gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically activeagent, the manner of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic material, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

[0199] The release of the therapeutically active agent from thecontrolled release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

[0200] The release-modifying agents which function as pore-formers maybe organic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

[0201] The sustained release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

[0202] The sustained release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

[0203] The release-modifying agent may also comprise a semi-permeablepolymer.

[0204] In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

[0205] The sustained release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864 (all of which are hereby incorporated by reference). Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

MATRIX FORMULATIONS

[0206] In other embodiments of the present invention, the controlledrelease formulation is achieved via a matrix having a controlled releasecoating as set forth above. The present invention also comprisessustained-release tablets comprising an opioid agonist and opioidantagonist particles coated with a coating that renders the antagonistsubstantially non-releasable, wherein the agonist and the antagonist aredispersed in a controlled release matrix that affords in-vitrodissolution rates of the opioid agonist within the preferred ranges andthat releases the opioid agonist in a pH-dependent or pH-independentmanner. The materials suitable for inclusion in a controlled releasematrix will depend on the method used to form the matrix.

[0207] For example, a matrix in addition to the opioid agonist and thesubstantially non-releasable form of the coated opioid antagonist, mayinclude:

[0208] Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which is capable of impartingcontrolled release of the opioid may be used in accordance with thepresent invention.

[0209] Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substitutedor unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

[0210] Of these polymers, acrylic polymers, especially Eudragit®RSPO—the cellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material.

[0211] When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° and 90° C. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

[0212] Preferably, the oral dosage form contains up to 60% (by weight)of at least one polyalkylene glycol.

[0213] The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

[0214] Preferred hydrophobic materials are water-insoluble with more orless pronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 30° to about 200° C., preferably from about 45° to about 90° C.Specifically, the hydrophobic material may comprise natural or syntheticwaxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl orpreferably cetostearyl alcohol), fatty acids, including but not limitedto fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about30° to about 100° C.

[0215] Suitable hydrophobic materials which may be used in accordancewith the present invention include digestible, long chain (C₈-C₅₀,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25° and 90° C. are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

[0216] Preferably, a combination of two or more hydrophobic materialsare included in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

[0217] One particular suitable matrix comprises at least one watersoluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylene glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 20% and 50% (by wt) of the total dosage.

[0218] In one embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

[0219] The at least one polyalkylene glycol may be, for example,polypropylene glycol or, which is preferred, polyethylene glycol. Thenumber average molecular weight of the at least one polyalkylene glycolis preferred between 1,000 and 15,000 especially between 1,500 and12,000.

[0220] Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

[0221] In another preferred embodiment, the matrix includes apharmaceutically acceptable combination of at least two hydrophobicmaterials.

[0222] In addition to the above ingredients, a controlled release matrixmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

PROCESSES FOR PREPARING MATRIX-BASED BEADS

[0223] In order to facilitate the preparation of a solid, controlledrelease, oral dosage form according to this invention, any method ofpreparing a matrix formulation known to those skilled in the art may beused. For example incorporation in the matrix may be effected, forexample, by (a) forming granules comprising at least one water solublehydroxyalkyl cellulose and opioid or an opioid salt; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂ -C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose/opioid with water. In a particularly preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the opioid.

[0224] In yet other alternative embodiments, a spheronizing agent,together with the active ingredient can be spheronized to formspheroids. Microcrystalline cellulose is preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (Trade Mark, FMC Corporation). In such embodiments, in additionto the active ingredient and pheronizing agent, the spheroids may alsocontain a binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

MELT EXTRUSION MATRIX

[0225] Sustained release matrices can also be prepared viamelt-granulation or melt-extrusion techniques, as long as the techniquesused do not damage the integrity of the substantially non-releasableform of the opioid antagonist added during the preparation of the matrixto the extent that sufficient amount of the opioid antagonist becomesavailable to be released into the gastrointestinal system upon oraladministration. Alternatively, the melt extrusion step may be performedwith the opioid agonist to produce sustained release particles of theagonist, which may then be combined with the substantiallynon-releasable form of the opioid antagonist. Generally,melt-granulation techniques involve melting a normally solid hydrophobicmaterial, e.g. a wax, and incorporating a powdered drug therein. Toobtain a sustained release dosage form, it may be necessary toincorporate an additional hydrophobic substance, e.g. ethylcellulose ora water-insoluble acrylic polymer, into the molten wax hydrophobicmaterial. Examples of sustained release formulations prepared viamelt-granulation techniques are found in U.S. Pat. No. 4,861,598,assigned to the Assignee of the present invention and herebyincorporated by reference in its entirety.

[0226] The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

[0227] In addition to the above ingredients, a sustained release matrixmay also contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

[0228] In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired.

[0229] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms are describedin the Handbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

MELT EXTRUSION MULTIPARTICULATES

[0230] The preparation of a suitable melt-extruded matrix according tothe present invention may, for example, include the steps of blendingthe opioid analgesic, together with at least one hydrophobic materialand preferably the additional hydrophobic material to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded toform strands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then blendedwith the opioid antagonist particles coated with a coating that rendersthe antagonist substantially non-releasable and divided into unit doses.The extrudate preferably has a diameter of from about 0.1 to about 5 mmand provides sustained release of the opioid agonist for a time periodof from about 8 to about 24 hours.

[0231] An optional process for preparing the melt extrusions of thepresent invention includes directly metering into an extruder ahydrophobic material, a therapeutically active agent, and an optionalbinder; heating the homogenous mixture; extruding the homogenous mixtureto thereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and combining the particles with the coated opioidantagonist particles and dividing them into unit doses. In this aspectof the invention, a relatively continuous manufacturing procedure isrealized.

[0232] The diameter of the extruder aperture or exit port can also beadjusted to vary the thickness of the extruded strands. Furthermore, theexit part of the extruder need not be round; it can be oblong,rectangular, etc. The exiting strands can be reduced to particles usinga hot wire cutter, guillotine, etc.

[0233] The melt extruded multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded multiparticulate(s)” and “melt-extruded multiparticulatesystem(s)” and “melt-extruded particles” shall refer to a plurality ofunits, preferably within a range of similar size and/or shape andcontaining one or more active agents and one or more excipients,preferably including a hydrophobic material as described herein. In thisregard, the melt-extruded multiparticulates will be of a range of fromabout 0.1 to about 12 mm in length and have a diameter of from about 0.1to about 5 mm. In addition, it is to be understood that themelt-extruded multiparticulates can be any geometrical shape within thissize range. Alternatively, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronization step.

[0234] In one preferred embodiment, oral dosage forms are prepared toinclude an effective amount of melt-extruded multiparticulates within acapsule. For example, a plurality of the melt-extruded multiparticulatesmay be placed in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

[0235] In another preferred embodiment, a suitable amount of themultiparticulate extrudate is combined with the coated opioid antagonistparticles and compressed into an oral tablet using conventionaltableting equipment using standard techniques. Techniques andcompositions for making tablets (compressed and molded), capsules (hardand soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

[0236] In yet another preferred embodiment, the coated opioid antagonistparticles are added during the extrusion process and the extrudate canbe shaped into tablets as set forth in U.S. Pat. No. 4,957,681(Klimesch, et al.), described in additional detail above and herebyincorporated by reference.

[0237] Optionally, the sustained release melt-extruded multiparticulatesystems or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained release coating such as the sustained releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic material to obtain a weight gain level from about2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular opioid analgesic compoundutilized and the desired release rate, among other things.

[0238] The melt-extruded unit dosage forms of the present invention mayfurther include combinations of melt-extruded multiparticulatescontaining one or more of the therapeutically active agents disclosedabove before being encapsulated. Furthermore, the unit dosage forms canalso include an amount of an immediate release opioid agonist for prompttherapeutic effect. The immediate release opioid agonist may beincorporated, e.g., as separate pellets within a gelatin capsule, or maybe coated on the surface of the multiparticulates after preparation ofthe dosage forms (e.g., controlled release coating or matrix-based). Theunit dosage forms of the present invention may also contain acombination of controlled release beads and matrix multiparticulates toachieve a desired effect.

[0239] The sustained release formulations of the present inventionpreferably slowly release the opioid agonist, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. The sustainedrelease profile of the melt-extruded formulations of the invention canbe altered, for example, by varying the amount of retardant, i.e.,hydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

[0240] In other embodiments of the invention, the melt extruded materialis prepared without the inclusion of the opioid agonist and/or coatedopioid antagonist particles, which are added thereafter to theextrudate. Such formulations typically will have the drugs blendedtogether with the extruded matrix material, and then the mixture wouldbe tableted in order to provide a slow release of the opioid agonist.Such formulations may be advantageous, for example, when thetherapeutically active agent included in the formulation is sensitive totemperatures needed for softening the hydrophobic material and/or theretardant material.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0241] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1

[0242] In Example 1, a substantially non-releasable form of an opioidantagonist (naltrexone HCl) is prepared by coating naltrexone particleswith a coating that renders the antagonist substantially non-releasable.Amt/unit Ingredients (mg) LOADING Naltrexone HCl  5.0 Sugar Spheres(30/35 50.0 mesh) Opadry White Y-5-7068  2.5 Purified Water  42.5*OVERCOATING Opadry White Y-5-7068  3.02 Purified Water  17.11*NON-RELEASE COATING (FOR RENDERING OPIOID ANTAGONIST SUBSTANTIALLYNON-RELEASABLE) Eudragit RS30D (dry wt.)  12.10 Triethyl Citrate  2.42Talc  4.84 Purified Water  49.21* OVERCOATING Opadry White Y-5-7068 4.12 Purified Water  23.35* Total 84.0

[0243] Process:

[0244] 1. Solution Preparation Dissolve the Naltrexone HCl in PurifiedWater. Once dissolved, add the Opadry White and continue mixing until ahomogeneous dispersion is yielded.

[0245] 2. Loading Apply the above dispersion onto the Sugar Spheresusing a fluid bed coating machine.

[0246] 3. Overcoating Prepare an overcoating solution by dispersingOpadry White in Purified Water. Apply this dispersion over the sugarspheres loaded with Naltrexone HCl using a fluid bed coating machine.

[0247] 4. Retardant Coating Prepare the non-release coating solution bymixing the Eudragit RS30D, Triethyl Citrate, Talc, and Purified Water.Apply this dispersion over the loaded and overcoated sugar spheres usinga fluid bed coating machine.

[0248] 5. Overcoating Prepare a second overcoating solution bydispersing Opadry White in Purified Water. Apply this dispersion overthe non-release coated naltrexone spheres using a fluid bed coatingmachine

[0249] 6. Curing Cure the spheres at 45° C. for approximately 48 hours.

[0250] The multiparticulates of Example 1 can be modified in order tohave an amount of naltrexoxe released which provides a desiredpharmacological effect as disclosed herein.

EXAMPLE 2

[0251] In Example 2, a substantially non-releasable form of an opioidantagonist (naltrexone HCl) is prepared as naltrexone HCl containinggranulates. The granulates are comprised of naltrexone HCl dispersed ina matrix that renders the antagonist substantially non-releasable.

[0252] Formula: Amt/unit Ingredient (mg) Naltrexone HCl 5.0 DicalciumPhosphate 53.0 Poly (DI-Lactide-Co- 12.0 Glycolide) polymer (PLGA)MW˜100,000 Ethyl Acetate Total 70.0

[0253] Process:

[0254] 1. Solution Preparation Dissolve PLGA in Ethyl Acetate by mixing.

[0255] 2. Granulation Place the Naltrexone HCl, and Dicalcium Phosphatein a fluid bed coating machine and granulate by spraying the abovesolution.

[0256] The multiparticulates of Example 2 can be modified in order tohave an amount of naltrexoxe released which provides a desiredpharmacological effect as disclosed herein.

EXAMPLE 3

[0257] In Example 3, a substantially non-releasable form of an opioidantagonist (naltrexone HCl) is prepared as naltrexone HCl extrudedpellets.

[0258] Formula: Amt/unit Ingredient (mg) Naltrexone HCl 5.0 EudragitRSPO 180.0 Stearyl Alcohol 55.0 Total 240.0

[0259] Process:

[0260] 1. Milling Pass stearyl alcohol flakes through an impact mill.

[0261] 2. Blending Mix Naltrexone HCl, Eudragit, and milled StearylAlcohol in a twin shell blender.

[0262] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant strands on a conveyor.

[0263] 4. Cooling Allow the strands to cool on the conveyor.

[0264] 5. Pelletizing Cut the cooled strands into pellets using aPelletizer.

[0265] 6. Screening Screen the pellets and collect desired sieveportion.

[0266] The multiparticulates of Example 3 can be modified in order tohave an amount of naltrexoxe Released which provides a desiredpharmacological effect as disclosed herein

EXAMPLE 4 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Beads and Releasable Naltrexone

[0267] Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 StearylAlcohol 44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered)Microcrystalline Cellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HClBeads 84.0 (Example 1) Magnesium Stearate  2.0 Opadry Red 10.0 PurifiedWater  56.7* Total 314.0 

[0268] Process:

[0269] 1. Milling Pass the Stearyl Alcohol flakes through an occillatingmill.

[0270] 2. Blending Mix the Hydrocodone Bitartrate, milled StearylAlcohol, Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, andGlycetyl Behenate in a twin shell blender.

[0271] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant heated material on a conveyor.

[0272] 4. Cooling Allow the extrudate to cool on the conveyor.

[0273] 5. Milling Mill the cooled extrudate using an occillating mill.

[0274] 6. Blending Blend the milled extrudate, naltrexone HCl beads(from Example 1), and Magnesium Stearate.

[0275] 7. Compression Compress the resultant granulation using a tabletpress.

[0276] 8. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0277] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 5 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Granulation

[0278] Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 StearylAlcohol 44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered)Microcrystalline Cellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HCl70.0 Granulation (Example 2) Magnesium Stearate  2.0 Opadry Red 10.0Purified Water  56.7* Total 300.0 

[0279] Process:

[0280] 1. Milling Pass the Stearyl Alcohol flakes through an occillatingmill.

[0281] 2. Blending Mix the Hydrocodone Bitartrate, milled StearylAlcohol, Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, andGlyceryl Behenate in a twin shell blender.

[0282] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant heated material on a conveyor.

[0283] 4. Cooling Allow the extrudate to cool on the conveyor.

[0284] 5. Milling Mill the cooled extrudate using an occillating mill.

[0285] 6. Blending Blend the milled extrudate, Naltrexone HClgranulation (from Example 2), and Magnesium Stearate.

[0286] 7. Compression Compress the resultant granulation using a tabletpress.

[0287] 8. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0288] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist, or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 6 Oxycodone HCl Controlled Release Tablets with Naltrexone HClBeads

[0289] Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose59.25 Povidone  5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin  2.00Stearyl Alcohol 25.00 Talc  2.50 Magnesium Stearate  1.25 Naltrexone HClBeads 84.00 (Example 1) Opadry Pink  6.00 Purified Water  34.00* Total215.00 

[0290] Process:

[0291] 1. Solution Preparation Plasticize the Eudragit with Triacetin bymixing.

[0292] 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, andPovidone into a fluid bed granulator and apply the above solution.

[0293] 3. Milling Pass the granulation through a rotating impeller mill.

[0294] 4. Drying Dry granulation if moisture content is too high.

[0295] 5. Waxing Melt Stearyl Alcohol and wax the above granulation byadding melted Stearyl Alcohol onto granulation while mixing.

[0296] 6. Cooling Cool the waxed granulation in a fluid bed dryer.

[0297] 7. Milling Pass the cooled waxed granulation through a rotatingimpeller mill.

[0298] 8. Blending Blend the milled waxed granulation, Talc, MagnesiumStearate. and Naltrexone HCl beads (from Example 1).

[0299] 9. Compression Compress the resultant granulation using a tabletpress.

[0300] 10. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0301] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an an amount to have adesired pharmacological effect as disclosed herein and can be immediateor sustained release.

EXAMPLE 7 Oxcodone HCl Controlled Release Tablets with Naltrexone HClGranulation

[0302] Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose59.25 Povidone  5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin  2.00Stearyl Alcohol 25.00 Talc  2.50 Magnesium Stearate  1.25 Naltrexone HCl70.00 Granulation (Example 2) Opadry Pink  6.00 Purified Water  34.00*Total 201.00 

[0303] Process:

[0304] 1. Solution Preparation Plasticize the Eudragit with Triacetin bymixing.

[0305] 2. Granulation Place Oxycodone HCl, Spray Dried Lactose andPovidone into a fluid bed granulator and apply the above solution.

[0306] 3. Milling Pass the granulation through a rotating impeller mill.

[0307] 4. Drying Dry granulation if moisture content is too high.

[0308] 5. Waxing Melt Stearyl Alcohol and wax the above granulation byadding melted Stearyl Alcohol onto granulation while mixing.

[0309] 6. Cooling Cool the waxed granulation in a fluid bed dryer.

[0310] 7. Milling Pass the cooled waxed granulation through a rotatingimpeller mill.

[0311] 8. Blending Blend the milled waxed granulation, Talc, MagnesiumStearate, and Naltrexone HCl granulation (from Example 2).

[0312] 9. Compression Compress the resultant granulation using a tabletpress.

[0313] 10. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0314] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an an amount to have adesired pharmacological effect as disclosed herein and can be immediateor sustained release.

EXAMPLE 8 Hydromorphone HCl Controlled Release Capsules with NaltrexoneHCl Extruded Pellets

[0315] Formula: Amt/unit Ingredient (mg) Hydromorphone HCl 12.0 EudragitRSPO 76.5 Ethylcellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets240.0 (Example 3) Hard Gelatin Capsules Total 360.0

[0316] Process:

[0317] 1. Milling Pass Stearyl Alcohol flakes through an impact mill.

[0318] 2. Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose andmilled Stearyl Alcohol in a twin shell blender.

[0319] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant strands on a conveyor.

[0320] 4. Cooling Allow the strands to cool on the conveyor.

[0321] 5. Pelletizing Cut the cooled strands into pellets using aPelletizer.

[0322] 6. Screening Screen the pellets and collect desired sieveportion.

[0323] 7. Encapsulation Fill the extruded Hydromorphone HCl pellets at120 mg and Naltrexone HCl pellets (from Example 3) at 240 mg into hardgelatin capsules.

[0324] The releasable naltrexone can be a) overcoated onto the pelletsby e.g., including it in the Opadry solution, b) modifying thesequestered component to release the desired naltrexone, c) includingthe naltrexone with the opioid agonist; or included in any other methodknown in the art. The amount of naltrexone should be in an amount tohave a desired pharmacological effect as disclosed herein and can beimmediate or sustained release.

EXAMPLE 9 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Beads

[0325] Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 StearylAlcohol 44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered)Microcrystalline Cellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HClBeads 84.0 (Example 1) Magnesium Stearate 2.0 Opadry Red 10.0 PurifiedWater 56.7* Total 314

[0326] Process:

[0327] 1. Milling Pass the Stearyl Alcohol flakes through an occillatingmill.

[0328] 2. Blending Mix the Hydrocodone Bitartrate, milled StearylAlcohol, Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, andGlyceryl Behenate in a twin shell blender.

[0329] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant heated material on a conveyor.

[0330] 4. Cooling Allow the extrudate to cool on the conveyor

[0331] 5. Milling Mill the cooled extrudate using an occillating mill.

[0332] 6. Blending Blend the milled extrudate, Naltrexone HCl beads(from Example 1), and Magnesium Stearate.

[0333] 7. Compression Compress the resultant granulation using a tabletpress.

[0334] 8. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0335] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 10 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Granulation

[0336] Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 StearylAlcohol 44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered)Microcrystalline Cellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HCl70.0 Granulation (Example 2) Magnesium Stearate 2.0 Opadry Red 10.0Purified Water 56.7* Total 300.5

[0337] Process:

[0338] 1. Milling Pass the Stearyl Alcohol flakes through an occillatingmill.

[0339] 2. Blending Mix the Hydrocodone Bitartrate, milled StearylAlcohol, Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, andGlyceryl Behenate in a twin shell blender

[0340] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant heated material on a conveyor.

[0341] 4. Cooling Allow the extrudate to cool on the conveyor.

[0342] 5. Milling Mill the cooled extrudate using an occillating mill.

[0343] 6. Blending Blend the milled extrudate, Naltrexone HClgranulation (from Example 2), and Magnesium Stearate.

[0344] 7. Compression Compress the resultant granulation using a tabletpress.

[0345] 8. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0346] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an an amount to have adesired pharmacological effect as disclosed herein and can be immediateor sustained release.

EXAMPLE 11 Oxycodone HCl Controlled Release Tablets with Naltrexone HClBeads

[0347] Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose58.75 Povidone 5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00Stearyl Alcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HClBeads 84.00 (Example 1) Opadry Pink 6.00 Purified Water 34.00* Total215.00

[0348] Process:

[0349] 1. Solution Preparation Plasticize the Eudragit with Triacetin bymixing.

[0350] 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, andPovidone into a fluid bed granulator and apply the above solution.

[0351] 3. Milling Pass the granulation through a rotating impeller mill.

[0352] 4. Drying Dry granulation if moisture content is too high.

[0353] 5. Waxing Melt Stearyl Alcohol and wax the above granulation byadding melted Stearyl Alcohol onto granulation while mixing.

[0354] 6. Cooling Cool the waxed granulation in a fluid bed dryer.

[0355] 7. Milling Pass the cooled waxed granulation through a rotatingimpeller mill.

[0356] 8. Blending Blend the milled waxed granulation, Talc, MagnesiumStearate, and Naltrexone HCl beads (from Example 1).

[0357] 9. Compression Compress the resultant granulation using a tabletpress.

[0358] 10. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0359] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 12 Oxycodone HCl Controlled Release Tablets with Naltrexone HClGranulation

[0360] Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose58.75 Povidone 5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00Stearyl Alcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HCl70.00 Granulation (Example 2) Opadry Pink 6.00 Purified Water 34.00*Total 201.00

[0361] Process:

[0362] 1. Solution Preparation Plasticize the Eudragit with Triacetin bymixing.

[0363] 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, andPovidone into a fluid bed granulator and apply the above solution.

[0364] 3. Milling Pass the granulation through a rotating impeller mill.

[0365] 4. Drying Dry granulation if moisture content is too high.

[0366] 5. Waxing Melt Stearyl Alcohol and wax the above granulation byadding melted Stearyl Alcohol onto granulation while mixing.

[0367] 6. Cooling Cool the waxed granulation in a fluid bed dryer.

[0368] 7. Milling Pass the cooled waxed granulation through a rotatingimpeller mill.

[0369] 8. Blending Blend the milled waxed granulation, Talc, MagnesiumStearate, and Naltrexone HCl granulation (from Example 2).

[0370] 9. Compression Compress the resultant granulation using a tabletpress.

[0371] 10. Coating Prepare a film coating solution by dispersing theOpadry in Purified Water and applying it to the tablet cores.

[0372] The releasable naltrexone can be a) overcoated onto the tablet bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an an amount to have adesired pharmacological effect as disclosed herein and can be immediateor sustained release.

EXAMPLE 13 Hydromorphone HCl Controlled Release Capsules with NaltrexoneHCl Extruded Pellets

[0373] Formula: Amt/unit Ingredient (mg) Hydromorphone HCl 12.0 EudragitRSPO 76.0 Ethylcellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets240.0 (Example 3) Hard Gelatin Capsules Total 360.0

[0374] Process:

[0375] 1. Milling Pass stearyl alcohol flakes through an impact mill.

[0376] 2. Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose andmilled Stearyl Alcohol in a twin shell blender.

[0377] 3. Extrusion Continuously feed the blended material into a twinscrew extruder and collect the resultant strands on a conveyor.

[0378] 4. Cooling Allow the strands to cool on a Conveyor.

[0379] 5. Pelletizing Cut the cooled strands into pellets using aPelletizer.

[0380] 6. Screening Screen the pellets and collect desired sieveportion.

[0381] 7. Encapsulation Fill the extruded Hydromorphone HCl pellets at120.0 mg and Naltrexone HCl pellets (from Example 3) at 240 mg into hardgelatin capsules.

[0382] The releasable naltrexone can be a) overcoated onto the pelletsby e.g., including it in the Opadry solution, b) modifying thesequestered component to release the desired naltrexone, c) includingthe naltrexone with the opioid agonist; or included in any other methodknown in the art. The amount of naltrexone should be in an amount tohave a desired pharmacological effect as disclosed herein and can beimmediate or sustained release.

EXAMPLE 14 Sequestered Naltrexone HCl Beads

[0383] In Example 14, Naltrexone HCl beads for incorporation intocapsules were prepared having the following formulation in Table 14below. TABLE 14 Amt/unit Ingredients (mg) Step 1. Drug layeringNaltrexone HCl 2.1 Non-pareil beads (30/35 mesh) 39.98 Opadry Clear 0.4(Hydroxypropylmethyl cellulose) Sodium ascorbate 0.027 Ascorbic acid0.05 Step 2. Anionic polymer Eudragit L30D (dry) 2.164 coat TriethylCitrate 0.433 Cabosil 0.108 Step 3. Sustained release Eudragit RS30D(dry) 17.475 coat Triethyl citrate 3.495 Cabosil 0.874 Step 4. Seal coatOpadry Clear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total(on dry basis) 69.287

[0384] Process:

[0385] 1. Dissolve naltrexone HCl, ascorbic acid, sodium ascorbate andOpadry Clear in water. Spray the drug solution onto non-pareil beads ina fluid bed coater with Wurster insert.

[0386] 2. Disperse Eudragit L30D, Triethyl citrate, and Cabosil inwater. Spray the dispersion onto the drug-loaded beads in the fluid bedcoater.

[0387] 3. Disperse Eudragit RS30D, triethyl citrate, and Cabosil inwater. Spray the dispersion onto the beads in the fluid bed coater.

[0388] 4. Dissolve Opadry Clear in water. Spray the solution onto thebeads in the fluid bed coater.

[0389] 5. Cure the beads at 60° C. for 24 hours.

EXAMPLE 15 Sequestered Naltrexone Multiparticulates

[0390] A naltrexone melt extruded multiparticulate formulation wasprepared. The melt extruded multiparticulate formulation is listed inTable 15 below. TABLE 15 Ingredients Amt/Unit (mg) Naltrexone HCl 2.0Eudragit RSPO 88.0 Stearyl alcohol 15.0 Stearic acid 15.0 BHT 1.0 Total121.0

[0391] Process:

[0392] 1. Blend milled Stearic acid, stearyl alcohol, Naltrexone HCl,BHT, and Eudragit RSPO using a V-blender.

[0393] 2. Extrude the mixture using a Powder Feeder, Melt Extruder(equipped with the 6×1 mm die head), Conveyor, Lasermike, andPelletizer.

[0394] Powder feed rate-4.2 kg/hr; vacuum-˜980 mBar

[0395] Conveyor-such that diameter of extrudate is 1 mm

[0396] Pelletizer-such that pellets are cut to 1 mm in length

[0397] 3. Screen pellets using #16 mesh and #20 mesh screens. Collectmaterial that passes through the #16 mesh screen and is retained on the#20 mesh screen.

[0398] 4. Fill size #2 clear gelatin capsules with the pellets. Range:NLT 114 mg and NMT 126 mg.

EXAMPLE 16 Sequestered Naltrexone CR Beads

[0399] A naltrexone sustained release bead formulation was preparedwhich can be incorporated into an opioid controlled release granulationand compressed into tablets. The naltrexone controlled release beadformulation is listed in Table 16 below. TABLE 16 Amt/unit* Ingredients(mg) Step 1. Drug layering Naltrexone HCl 0.609 Non-pareil beads (30/35mesh) 67.264 Opadry Clear 0.547 Step 2. Seal coat Eudragit L 2.545Triethyl citrate 0.636 Glyceryl monostearate 0.239 Step 3. Sustainedrelease Eudragit RS30D (dry) 43.789 coat Triethyl citrate 8.758 Cabosil2.189 Step 4. Seal coat Opadry Clear 2.053 (Hydroxypropylmethylcellulose) Cabosil 1.365 Total 130

[0400] Process:

[0401] 1. Dissolve naltrexone HCl and Opadry (HPMC) in water. Spray thedrug solution onto non-pareil beads in a fluid bed coater with Wursterinsert.

[0402] 2. Disperse Eudragit L, Triethyl citrate, and glycerylmonostearate in water. Spray the dispersion onto the drug-loaded beadsin the fluid bed coater.

[0403] 3. Disperse Eudragit RS, trietbyl citrate, and Cabosil in water.Spray the dispersion onto the beads in the fluid bed coater.

[0404] 4. Dissolve Opadry in water. Spray the solution onto the beads inthe fluid bed coater.

[0405] 5. Cure the beads at 60° C. for 24 hours.

EXAMPLE 17 Controlled Release Oxycodone 20 mg

[0406] In Example 17, a sustained release 20 mg oxycodone formulationwas prepared having the formulation listed in Table 17 below. TABLE 17Ingredients Amt/Unit (mg) Oxycodone HCl 20.0 Spray Dried Lactose 59.25Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 Stearyl Alcohol25.0 Talc 2.5 Magnesium Stearate 1.25 Opadry Pink Y-S-14518A 4.0 Total129.0

[0407] Process:

[0408] 1. Granulation: Spray the Eudragit/Triacetin dispersion onto theOxycodone HCl, Spray Dried Lactose and Povidone using a fluid bedgranulator.

[0409] 2. Milling: Discharge the granulation and pass through a mill.

[0410] 3. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool.

[0411] 4. Milling: Pass the cooled granulation through a mill.

[0412] 5. Lubrication: Lubricate the granulation with talc and magnesiumstearate using a mixer.

[0413] 6. Compression: Compress the granulation into tablets using atablet press.

[0414] 7. Film coating: Apply an aqueous film coat to the tablets.

EXAMPLE 18

[0415] In Example 18, naltrexone beads prepared in accordance withExample 16 are incorporated into the sustained release 20 mg oxycodonetablets prepared in accordance with Example 17 and having the formulalisted in Table 18 below. TABLE 18 Amt/unit* Ingredients (mg) Step 1.Ganulation Oxycodone HCl 20.0 Spray Dried Lactose 59.25 Povidone 5.0Eudragit RS30D (dry) 10.0 Triacetin 2.0 Stearyl alcohol 25.0 Talc 2.5Magnesium 1.25 Step 2. Combination OxyContin granulation (Example 125tablet 3) Naltrexone CR beads (Formula 2) 140

[0416] Process:

[0417] b 1. Spray the Eudragit/triacetin dispersion onto the OxycodoneHCl, spray dried lactose and povidone using a fluid bed granulator.

[0418] 2. Discharge the granulation and pass through a mill.

[0419] 3. Melt the stearyl alcohol and add to the milled granulationusing a mill. Allow to cool.

[0420] 4. Pass the cooled granulation through a mill.

[0421] 5. Lubricate the granulation with talc and magnesium stearate.Using a mixer.

[0422] 6. Mix naltrexone beads with the above granulation and compressinto tablets.

[0423] Alternate Process:

[0424] 1. Spray the Eudragit/triacetin dispersion onto the OxycodoneHCl, spray dried lactose and povidone using a fluid bed granulator.

[0425] 2. Discharge the granulation and pass through a mill.

[0426] 3. Mix naltrexone beads (example 2) with the above granulation ina Hobar mixer.

[0427] 4. Melt the stearyl alcohol and add to the above mixture. Allowto cool.

[0428] 5. Pass the cooled granulation through a mill.

[0429] 6. Lubricate the granulation with talc and magnesium stearateusing a mixer.

[0430] 7. Compress into tablets.

[0431] Releasable naltrexone can be a) overcoated onto the tablets bye.g., including it in the Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 19 Controlled Release Hydrocodone

[0432] A sustained release hydrocodone formulation was prepared havingthe formula in Table 19 below. TABLE 19 Ingredients Amt/Unit (mg)Amt/Batch (g) Hydrocodone Bitartrate 15.0 320.0 Eudragit RSPO 76.01520.0 Eudragit RLPO 4.0 80.0 Stearyl Alcohol 25.0 500.0 Total 120.02400.0

[0433] Process:

[0434] 1. Blend milled Stearyl Alcohol, Eudragit RLPO, HydrocodoneBitartrate, and Eudragit RSPO using a Hobart Mixer.

[0435] 2. Extrude the granulation using a Powder Feeder, Melt Extruder(equipped with the 6×1 mm die head), Conveyor, Lasermike, andPelletizer.

[0436] Powder feed rate-40 g/min; vacuum-˜980 mBar

[0437] Conveyor-such that diameter of extrudate is 1 mm

[0438] Pelletizer-such that pellets are cut to 1 mm in length

[0439] 3. Screen pellets using #16 mesh and #20 mesh screens. Collectmaterial that passes through the #16 mesh screen and is retained on the#20 mesh screen.

[0440] 4. Fill size #2 clear gelatin capsules with the pellets. Range:NLT (not less than) 114 mg and NMT (not more than) 126 mg.

[0441] The sequestered naltrexone formulation of Example 15 can beincorporated in a capsule with the hydrocodone pellets. Preferably, thesequestered naltrexone pellets are indistinguishable from thehydrocodone pellets.

[0442] Releasable naltrexone can be a) overcoated onto the pellets bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 20 Controlled Release Oxycodone HCl Beads

[0443] A sustained release oxycodone HCl bead formulation was preparedhaving the formula in Table 20 below. TABLE 20 Amt/unit* Ingredients(mg) Step 1. Drug layering Oxycodone HCl 10.5 Non-pareil beads (30/35mesh) 45.349 Opadry Clear 2.5 Step 2. Sustained release Eudragit RS30D(dry) 7.206 coat Eudragit RL30D (dry) 0.379 Triethyl citrate 1.517Cabosil 0.379 Step 3. Seal coat Opadry Clear 1.899 (Hydroxypropylmethylcellulose) Cabosil 0.271 Total 70.0

[0444] Process:

[0445] 1. Dissolve oxycodone HCl and Opadry (HPMC) in water. Spray thedrug solution onto non-pareil beads in a fluid bed coater with Wursterinsert.

[0446] 2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, andCabosil in water. Spray the dispersion onto the beads in the fluid bedcoater.

[0447] 3. Dissolve Opadry in water. Spray the solution onto the beads inthe fluid bed coater.

[0448] 4. Cure the beads at 60° C. for 24 hours.

[0449] The sequestered naltrexone formulation of Example 14 can beincorporated in a capsule with the oxycodone beads. Preferably, thesequestered naltrexone beads are indistinguishable from the oxycodonebeads.

[0450] Releasable naltrexone can be a) overcoated onto the beads bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

EXAMPLE 21 Controlled Release Hydromorphone

[0451] A sustained release hydromorphone HCl formulation was preparedhaving the formula in Table 21 below: TABLE 21 Ingredients Amt/Unit (mg)Hydromorphone HCl 12.0 Eudragit RSPO 76.5 Ethocel 4.5 Stearic acid 27.0Total 120.0

[0452] Process:

[0453] 1. Blend milled Stearic acid, ethocel, Hydrocodone Bitartrate,and Eudragit RSPO using a V-blender.

[0454] 2. Extrude the mixture using a Powder Feeder, MeltExtruder(equipped with the 6×1 mm die head), Conveyor, Lasermike, andPelletizer.

[0455] Powder feed rate-4.2 kg/hr; vacuum-˜980 mBar

[0456] Conveyor-such that diameter of extrudate is 1 mm

[0457] Pelletizer-such that pellets are cut to 1 mm in length

[0458] 3. Screen pellets using #16 mesh and #20 mesh screens. Collectmaterial that passes through the #16 mesh screen and is retained on the#20 mesh screen.

[0459] 4. Fill size #2 clear gelatin capsules with the pellets. Range:NLT 114 mg and NMT 126 mg.

[0460] The sequestered naltrexone formulation of Example 15 can beincorporated in a capsule with the hydromorphone pellets. Preferably,the sequestered naltrexone pellets are indistinguishable from thehydrocodone pellets.

[0461] Releasable naltrexone can be a) overcoated onto the pellets bye.g., including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

What is claimed is:
 1. An oral dosage form, comprising (i) atherapeutically effective amount of an opioid agonist; (ii) an opioidantagonist in releasable form; and (iii) a sequestered opioid antagonistwhich is not released when the dosage form is administered intact.
 2. Anoral dosage form, comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist; (ii) a secondcomponent comprising an opioid antagonist in releasable form; and (iii)a third component comprising a sequestered opioid antagonist which isnot released when the dosage form is administered intact.
 3. An oraldosage form, comprising (i) a first component comprising atherapeutically effective amount of an opioid agonist; (ii) a secondcomponent comprising an opioid antagonist in releasable form, and asequestered opioid antagonist which is not released when the dosage formis administered intact.
 4. An oral dosage form, comprising (i) a firstcomponent comprising a therapeutically effective amount of an opioidagonist and an opioid antagonist in releasable form; and (ii) a secondcomponent comprising a sequestered opioid antagonist which is notreleased when the dosage form is administered intact.
 5. An oral dosageform, comprising (i) a first component comprising a therapeuticallyeffective amount of an opioid agonist and an opioid antagonist inreleasable form; and (ii) a second component comprising a sequesteredopioid antagonist which is not substantially released when the dosageform is administered intact.
 6. An oral dosage form, comprising (i) afirst component comprising a therapeutically effective amount of anopioid agonist; (ii) a second component comprising an opioid antagonistin releasable form; and (iii) a third component comprising a sequesteredopioid antagonist which is not substantially released when the dosageform is administered intact.
 7. The dosage form of claim 1 wherein thequantity of antagonist released from said dosage form is in a ratio tosaid agonist which is aversive in physically dependent human subjectswhen the dosage form is administered at the same amount or at a higheramount than said therapeutically effective amount
 8. The dosage form ofclaim 5 wherein the quantity of said antagonist released from said firstcomponent is in an amount sufficient to be aversive in physicallydependent human subjects when the dosage form is administered at thesame amount or at a higher amount than said therapeutically effectiveamount.
 9. The dosage form of claim 5 wherein the quantity of saidantagonist released from said first component is less than the amountsufficient to be aversive in physically dependent human subjects whenthe dosage form is administered at the same amount or at a higher amountthan said therapeutically effective amount.
 10. The dosage form of claim6 wherein the amount of said antagonist released from said secondcomponent is in an amount sufficient to be aversive in physicallydependent human subjects when the dosage form is administered at thesame amount or at a higher amount than said therapeutically effectiveamount.
 11. The dosage form of claim 6 wherein the amount of saidantagonist released from said second component is less than the amountsufficient to be aversive in physically dependent human subjects whenthe dosage form is administered at the same amount or at a higher amountthan said therapeutically effective amount.
 12. The dosage form of claim1 further comprising a sustained release excipient which provides asustained release of said opioid agonist.
 13. The dosage form of claim 1further comprising a sustained release excipient which provides asustained release of said opioid antagonist.
 14. The dosage form ofclaim 1 further comprising a sustained release excipient which providesa sustained release of said opioid agonist and said opioid antagonist.15. The dosage form of claim 1 wherein said sequestered antagonist is inthe form of multiparticulates individually coated with a material thatprevents release of the sequestered antagonist.
 16. The dosage form ofclaim 1 wherein said sequestered antagonist is in the form ofmultiparticulates individually coated with a material that substantiallyprevents release of said sequestered antagonist.
 17. The dosage form ofclaim 1 wherein said sequestered antagonist is dispersed in a matrixcomprising a sequestering material that prevents the release of saidsequestered antagonist.
 18. The dosage form of claim 1 wherein saidsequestered antagonist is dispersed in a matrix comprising asequestering material that substantially prevents the release of saidsequestered antagonist.
 19. The dosage form of claim 1 wherein saidreleasable opioid antagonist is the same as the sequestered antagonist.20. The dosage form of claim 1 wherein said releasable opioid antagonistis different than the sequestered antagonist.
 21. The dosage form ofclaim 19 wherein said antagonist is selected from the group consistingof naltrexone, naloxone, nalmephene, cyclazocine, levallorphan,pharmaceutically acceptable salts thereof and mixtures thereof.
 22. Thedosage form of claim 20 wherein said releasable antagonist is selectedfrom the group consisting of naltrexone, naloxone, nalmephene,cyclazocine, levallorphan, pharmaceutically acceptable salts thereof andmixtures thereof and said sequestered antagonist is selected from thegroup consisting of naltrexone, naloxone, nalmephene, cyclazocine,levallorphan, pharmaceutically acceptable salts thereof and mixturesthereof.
 23. The dosage form of claim 1 wherein said opioid is selectedfrom the group consisting of morphine, hydromorphone, hydrocodone,oxycodone, codeine, levorphanol, tramadol, meperidine, methadone,pharmaceutically acceptable salts thereof and mixtures thereof.
 24. Thedosage form of claim 1 having a ratio of having a ratio of releasableopioid antagonist to opioid agonist that is analgesically effective whenthe combination is administered orally, but which is aversive inphysically dependent human subjects when administered at the same amountor at a higher amount than said therapeutically effective amount. 25.The dosage form of claim 24 wherein said ratio of releasable opioidantagonist to opioid agonist maintains an analgesic effect but does notincrease analgesic efficacy of the opioid agonist relative to the sametherapeutic amount of opioid analgesic when administered to humanpatients without said opioid antagonist.
 26. The oral dosage form ofclaim 1 wherein the opioid agonist is hydrocodone and the releasableantagonist is naltrexone.
 27. The oral dosage form of claim 26, whereinthe ratio of releasable naltrexone to hydrocodone is from about 0.03:1to about 0.27:1.
 28. The oral dosage form of claim 27, wherein the ratioof releasable naltrexone to hydrocodone is from about 0.05:1 to about0.20:1.
 29. The oral dosage form of claim 7, wherein said releasableopioid antagonist is naltrexone and said opioid agonist is oxycodone,wherein the ratio of releasable naltrexone to oxycodone is from about0.037:1 to about 0.296:1.
 30. The oral dosage form of claim 7, whereinsaid releasable opioid antagonist is naltrexone and said releasableopioid agonist is codeine, wherein the ratio of releasable naltrexone tocodeine is from about 0.005:1 to about 0.044:1.
 31. The oral dosage formof claim 7, wherein said releasable opioid antagonist is naltrexone andsaid opioid agonist is hydromorphone, wherein the ratio of releasablenaltrexone to hydromorphone is from about 0.148:1 to about 1.185:1. 32.The oral dosage form of claim 7, wherein said releasable opioidantagonist is naltrexone and said opioid agonist is levorphanol, whereinthe ratio of releasable naltrexone to levorphanol is from about 0.278:1to about 2.222:1.
 32. The oral dosage form of claim 7, wherein saidreleasable opioid antagonist is naltrexone and said opioid agonist ismeperidine, wherein the ratio of releasable naltrexone to meperidine isfrom about 0.0037:1 to about 0.0296:1.
 33. The oral dosage form of claim7, wherein said releasable opioid antagonist is naltrexone and saidopioid agonist is methadone, wherein the ratio of releasable naltrexoneto methadone is from about 0.056:1 to about 0.444:1.
 34. The oral dosageform of claim 7, wherein said releasable opioid antagonist is naltrexoneand said opioid agonist is morphine, wherein the ratio of releasablenaltrexone to morphine is from about 0.018:1 to about 0.148:1.
 35. Theoral dosage form of claim 7, wherein said releasable opioid antagonistis naltrexone and said opioid agonist is oxycodone, wherein the ratio ofreleasable naltrexone to oxycodone is from about 0.056:1 to about0.222:1.
 36. The oral dosage form of claim 7, wherein said releasableopioid antagonist is naltrexone and said opioid agonist is codeine,wherein the ratio of releasable naltrexone to codeine is from about0.0083:1 to about 0.033:1.
 37. The oral dosage form of claim 7, whereinsaid releasable opioid antagonist is naltrexone and said opioid agonistis hydromorphone, wherein the ratio of releasable naltrexone tohydromorphone is from about 0.222:1 to about 0.889:1.
 38. The oraldosage form of claim 7, wherein said releasable opioid antagonist isnaltrexone and said opioid agonist is levorphanol, wherein the ratio ofreleasable naltrexone to levorphanol is from about 0.417:1 to about1.667:1.
 39. The oral dosage form of claim 7, wherein said releasableopioid antagonist is naltrexone and said opioid agonist is meperidine,wherein the ratio of releasable naltrexone to meperidine is from about0.0056:1 to about 0.022:1.
 40. The oral dosage form of claim 7, whereinsaid releasable opioid antagonist is naltrexone and said opioid agonistis methadone, wherein the ratio of releasable naltrexone to methadone isfrom about 0.083:1 to about 0.333:1.
 41. The oral dosage form of claim7, wherein said releasable opioid antagonist is naltrexone and saidopioid agonist is morphine, wherein the ratio of releasable naltrexoneto morphine is from about 0.028:1 to about 0.111:1.
 42. The oral dosageform of claim 1 wherein the releasable antagonist is in an amount toattenuate a side effect of said opioid agonist selected from the groupconsisting of anti-analgesia, hyperalgesia, hyperexcitability, physicaldependence, tolerance, and a combination of any of the foregoing. 43.The controlled release dosage form of claim 1, wherein the amount ofantagonist released during the dosing interval enhances the analgesicpotency of the opioid agonist.
 44. The controlled-release dosage form ofclaim 42, wherein the amount of the releasable opioid receptorantagonist is about 100 to about 1000 fold less than the amount of theopioid agonist.
 45. The dosage form of claim 7 wherein the ratio of theamount of antagonist released from said dosage form after tampering tothe amount of said antagonist released from said intact dosage form isabout 4:1 (w:w) or greater, based on the in-vitro dissolution at 1 hourof said dosage form in 900 ml of Simulated Gastric Fluid using a USPType II (paddle) apparatus at 75 rpm at 37 degrees C.
 46. The dosageform of claim 7 wherein the ratio of the amount of antagonist containedin said intact dosage form to the amount of said antagonist releasedfrom said intact dosage form after 1 hour is about 4:1 or greater, basedon the in-vitro dissolution at 1 hour of said dosage form in 900 ml ofSimulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpmat 37 degrees C.
 47. The oral dosage form of claim 45 wherein said ratiois 10:1 or greater.
 48. The oral dosage form of claim 45 wherein saidratio is 50:1 or greater.
 49. The oral dosage form of claim 45 whereinsaid ratio is 100:1 or greater.
 50. The oral dosage form of claim 1wherein said releasable antagonist is naloxone or a pharmaceuticallyacceptable salt thereof and said non-releasable antagonist is naltrexoneor a pharmaceutically acceptable salt thereof.
 51. A method of treatingpain comprising administering a dosage form of claim
 1. 52. A method ofdeterring abuse comprising preparing a dosage form of claim
 1. 53. Amethod of preparing a dosage form of claim 1 comprising combining anopioid agonist with an antagonist in releasable and non-releasable formin a dosage form.